Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia

Daniel Steinberg, Christopher K. Glass and Joseph L. Witztum

Circulation. 2008;118:672-677
doi: 10.1161/CIRCULATIONAHA.107.753152
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 Contemporary Reviews in Cardiovascular Medicine
Evidence Mandating Earlier and More Aggressive
Treatment of Hypercholesterolemia
Daniel Steinberg, MD, PhD; Christopher K. Glass, MD, PhD; Joseph L. Witztum, MD
T he long-standing controversy over the validity of the
lipid hypothesis of atherosclerosis has been settled.13 In
several large-scale, 5-year trials, statins have reduced coro-
nary heart disease (CHD) morbidity and mortality by 30%,
and the magnitude of the protective effect mirrored the
magnitude of the low-density lipoprotein (LDL) lowering.4
However, as has been quite correctly pointed out,5,6 some
70% of those expected to have an event (based on the number
of events in the control group) went on to have one during the
5 years of the trial despite statin therapy. For example, in the
Scandinavian Simvastatin Survival Study, 502 events oc-
curred in the untreated group and 353 in the statin-treated
group. The number of events prevented (n149), as a
percentage of the number expected, was 29.7% (149/
502100); the number of events in the statin group that were
not prevented (353) amounts to 70.3% (353/502100).
Looked at this way, the results are admittedly not quite so
impressive. In fact, some investigators are now taking the
position that we can expect to achieve higher salvage rates
only if we supplement LDL-lowering therapies with alterna-
tive interventions such as the use of antiinflammatory agents
or immunotherapy. This may turn out to be true. However, it
is much too early to reach that conclusion for reasons we
discuss here. The search for alternative or supplementary
therapies is already in full swing and should continue.6 8 We
are confident that one day these additional therapies will take
their place alongside cholesterol-lowering agents in our
armamentarium. However, we believe that the results of the
statin trials to date considerably underestimate the full poten-
tial of cholesterol-lowering strategies. It would be unfortunate
if efforts to fully exploit that potential faltered because of a
misplaced pessimism based on the statin results to date. Our
current approaches may be a case of too little, too late.5,9 14
How much further can we expect to decrease risk by treating
dyslipidemia (ie, lowering LDL levels and/or raising high-
density lipoprotein levels)?
Why Do We Think We Can Do Better?
One important line of evidence comes from a consideration of
the Japanese experience. In 1952, mortality from CHD
among Japanese men 55 to 64 years of age was 10% of
what it was in the United States.15,16 Their total cholesterol
levels at the time averaged 160 mg/dL (estimated LDL,
From the Department of Medicine, University of California San Diego, La Jolla.
Correspondence to Dr Daniel Steinberg, Department of Medicine, BSB 1080, University of California San Diego, 9500 Gilman Dr, La Jolla, CA
92093 0682. E-mail dsteinberg@ucsd.edu
(Circulation. 2008;118:672-677.)
2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
672
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80 mg/dL). It is noteworthy that the Japanese enjoyed this
relative immunity to CHD despite the fact that the prevalence
of one of the major risk factors cigarette smokingwas
much higher in Japan than in Western countries,17 and
another-hypertensionwas just as high.18 Even the dia-
betic population in Japan fares better than the diabetic
population in Western countries. In 1985, almost 30% of
British male diabetics but only 15% of the Japanese male
diabetics had CHD.19 The implication is that if blood choles-
terol levels are sufficiently low, the other dominant risk
factors, including cigarette smoking, hypertension, and dia-
betes mellitus, constitute much less of a threat.
Are these large differences in incidence between Japan and
Western countries based primarily on genetic factors? No.
Two cleverly designed epidemiological studies showed that
the Japanese who had migrated and taken up permanent
residence in Hawaii had higher blood cholesterol levels and a
higher incidence of CHD than those who remained on the
home island. For those who migrated even further, on to
California, the differences were even more striking.20,21 This
and other migration studies22 showed that the differences in
CHD risk among different populations are certainly not
entirely genetic. Which environmental factors are at play? A
number of factors could be involved, but there is reason to
believe that the major factors are changes in diet and exercise
patterns that predispose to elevated blood cholesterol and
obesity. Keys23 reported as early as 1957 that the fat content
of the diet, as a percentage of total calories, rose from 10% to
15% in Japanese on the home island to 30% in Japanese
migrants to Hawaii and to almost 40% in migrants to Los
Angeles.
A crucially important point needs to be noted here: For
whatever reasons, the Japanese have their lower cholesterol
levels for their entire lifetimes. Lowering the cholesterol level
of a 50-year-old American for just 5 years, even if his
cholesterol is successfully brought down to a Japanese-like
level, is unlikely to convert his risk to a Japanese-like risk. At
50 years of age, he most likely enters the study with
well-established, extensive arterial disease.24,25 It would be
unreasonable to expect that all that damage could be reversed
in just 5 years. The canonical 5-year trials have given us a
minimum estimate of the impact of preventive management.
Only after longer trials with younger subjects will we have
DOI: 10.1161/CIRCULATIONAHA.107.753152
 Steinberg et al
some estimate of the maximum potential. We will return later
to this key issue, the need for earlier treatment.
How Much More Aggressive Should
Treatment Be?
In the 1940s, many clinical laboratories defined a total
cholesterol level of 280 mg/dL as the upper limit of normal.
That number has come tumbling down over the decades as
epidemiological and clinical trial experience has accumu-
lated. Currently, for individuals at high risk, the widely
accepted rule is becoming the lower, the better.4,11,26 31 The
National Institutes of Health (NIH) now recognizes that an
LDL of 70 mg/dL confers more benefit than the canonical
100 mg/dL originally recommended in the Adult Treatment
Panel III 2001 guidelines.32,33 Careful analysis of the statin
data makes it clear that further benefit is conferred when LDL
is reduced even to 40 to 60 mg/dL.29 Although limited, data
are available suggesting that patients with initial LDL levels
40 mg/dL show lower all-cause mortality after 2 years of
statin therapy.34
With combination therapy, it is now possible to reach these
low LDL goals; they are not unrealistic.35 Yet, most patients
outside specialty clinics are not reaching those goals, in part
because of poor compliance but also in part because practi-
tioners are still hesitant to be more aggressive. There continue
to be concerns about safety and side effects despite the wealth
of evidence that they are not serious problems in the vast
majority of patients.36
Do Adverse Effects Accompany
Cholesterol Lowering?
Is lowering LDL levels intrinsically dangerous? That possi-
bility has been suggested in the past, but no hard evidence
exists for such a concern, and a number of considerations
make such an effect quite improbable.
First, levels of intracellular cholesterol are jealously
guarded by the wonderfully efficient LDL receptor homeo-
static mechanism elucidated by Brown and Goldstein.37
Consequently, lowering plasma cholesterol levels does not
decrease intracellular cholesterol levels. The LDL receptor
has a very high affinity for its ligand, so much so that even at
plasma LDL cholesterol concentrations of 10 mg/dL, the
LDL receptors in peripheral tissues would still be 50%
saturated and uptake would continue unabated.
Second, we know that most mammalian species have LDL
levels well below those reached in humans during even the
most aggressive treatment of hypercholesterolemia (mean
value, 42 mg/dL).38 Obviously, these animals cells do just
fine. In addition, cord-blood LDL levels in humans are 20%
of adult levels,39 showing that growth and development of the
fetus are just fine at LDL cholesterol levels 40 mg/dL.
Third, in some kindreds with hypobetalipoproteinemia,
LDL cholesterol levels can be 15 mg/dL throughout life,
yet the affected members show perfectly normal growth and
development and actually have increased longevity.40,41
We know now from the large-scale statin trials that
lowering LDL values to well below 100 mg/dL not only is
safe but actually decreases overall mortality significant-
ly.4,11,29,42 46 Thus, there should be no hesitation at all about
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Earlier Treatment of Hypercholesterolemia 673
lowering LDL levels through attention to lifestyle changes
(ie, diet and exercise), in which the intervention itself carries
no risks. Here, the only rule necessary is the lower, the
better.
However, when it comes to drug therapy, we must take a
hard look at risks and benefits. In patients at high or moderate
risk of CHD, the risk-to-benefit ratio with statins is obviously
favorable, and their use should be expanded. If target goals
are not achieved, combination therapies with other hypolipi-
demic agents should be aggressively pursued. In short, for
most subjects, hypolipidemic agents, alone or in combination,
are on hand to lower cholesterol levels to meet current
guidelines and even the more aggressive guidelines that are
sure to come.
Should We Be Starting Preventive
Measures Earlier?
Fatty streak lesions are already extensive by 30 years of
age.24,25 These lesions are themselves asymptomatic and
clinically nonthreatening at that early stage. Consequently,
some have proposed that intervention can be deferred and that
treatment will somehow catch up. This is shortsighted. It
overlooks the fact that the early lesions are the precursors of
the later, clinically threatening lesions. Thus, the risk factors
that predict the extent of fatty streaks in the young, including
hypercholesterolemia, are the same as those that predict
coronary heart disease risk and myocardial infarction in
adults.47,48 It is not as though we were dealing with two
different diseases, one early and clinically benign (and, by
implication, therefore not requiring our immediate attention)
and 1 late that now carries a more imminent threat of angina
and infarction (and therefore demands our immediate attention).
No, we are dealing with a single disease entity that evolves
slowly over decades. Mapping in the Pathobiological Deter-
minants of Atherosclerosis in Youth study49 confirmed what
was known from animal model studies, namely that the
anatomic sites favored for fatty streak development are much
the same as those favored for fibrous plaque development. In
short, the fatty streak is indeed the precursor of the plaque.
The disease is a continuum, so prevention of (or slowing the
development of) fatty streaks will prevent (or slow the
development of) the later, clinically significant lesions. So,
why wait for the clinical expression to be just around the
corner? No one would seriously propose deferring cancer
therapy until the tumor had reached a certain size. No one
would advocate deferring treatment of diabetes mellitus until
microvascular disease was evident. Why not slow things
down early in the game, as urged by McGill and McMahan9
and by Domanski14? The hope is that doing so might prevent
clinical expression or at least defer it into the 9th or 10th
decade.
We already treat very high-risk patients in childhood (eg,
patients with familial hypercholesterolemia), and evidence is
building to show that early treatment works and is safe. In
children 8 to 18 years of age, pravastatin treatment for 2 years
lowered LDL levels by 24% and significantly slowed the rate
of progression of intima-media thickening of the carotid
artery.50 No adverse effects on growth, hormone levels, or
sexual maturation were found. A follow-up study when the
674 Circulation August 5, 2008
whole cohort had been on statin treatment for an additional
2.5 years showed that the results were significantly better in
the children entered into the study at younger ages.10 Until
long-term studies have been done, we cannot say with
certainty how much better the cardiac end-point results will
be as a result of starting earlier. Still, some exciting new
results suggest that we may be pleasantly surprised.
A new gene importantly involved in regulation of the LDL
receptor has recently been identified.51,52 This gene, PCSK9,
codes for a secreted protease that acts to decrease the number
of LDL receptors expressed in the liver. Overexpression of
the gene (or gain-of-function mutations) lowers LDL receptor
number and thus raises plasma LDL levels; knocking out the
gene (or a loss-of-function mutation) increases LDL receptor
number and thus lowers LDL levels. PCSK9 does not regulate
at the transcriptional or translational level but rather in some
fashion suppresses the level of expression of the LDL
receptor at the surface of the hepatocyte. The precise molec-
ular mechanisms are still uncertain.
The key point here is that Cohen and colleagues53,54 have
studied CHD risk in subjects with nonsense mutations in
PCSK9 that cause low plasma LDL levels, presumably from
birth. The LDL levels in these subjects were reduced by 28%.
The CHD risk, on the other hand, was reduced by fully 88%.
In the 5-year statin trials, the drop in LDL (25% to 35%) was
similar, but the decrease in risk was only 30%, not 88%. As
nicely pointed out by Brown and Goldstein,12 the implication
is that having a low LDL from birth almost triples the
magnitude of the effect on risk compared with the risk
reduction found in a 5-year trial of middle-aged people.
Nonsense mutations were much less common in the white
subjects in the Cohen et al cohort, but a missense mutation
(R46L) occurred in 3.2% of the whites. This mutation was
associated with a 15% lower LDL and a 47% reduction in
CHD risk. Again, the large impact of this modest reduction in
LDL on risk is striking. The protective effect of the R46L
mutation has been confirmed by 2 groups.55,56 These findings
strongly support a mandate to treat earlier. Drugs that regulate
the expression and function of PSCK9 may fairly soon join
the ranks of cholesterol-lowering agents. Working by a
different mechanism, PCSK9 inhibitors would probably have
effects additive to those of other drugs.
Will Correction of Hypercholesterolemia Ever
Be Sufficient Without Additional
Interventions Directed at the
Inflammatory Element?
Even with the most intensive treatment available, anatomic
regression in humans as judged by angiography is very slow,
but it definitely occurs. Armstrong et al57 and Armstrong and
Megan58 showed that in cholesterol-fed nonhuman primates,
virtually total regression could ultimately be achieved, but it
took 40 months after return to a cholesterol-free diet to undo
the damage done during 17 months of prior cholesterol
feeding. The remarkable thing about these studies is that not
only was almost all of the lipid gone from the arteries but also
virtually all signs of the inflammatory process were gone. The
remains of the lesions were basically scar tissue with no signs
of cellular infiltrates. In other words, it appeared that in the
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absence of continuing hypercholesterolemia, the inflamma-
tory process was not self-sustaining. Simply arresting the
hypercholesterolemia by reverting to a normal monkey chow
diet caused virtually complete lesion regression without the
need for intervention directed specifically at the inflamma-
tory process, results recently confirmed in an elegant series of
studies in rabbits.59 61 As discussed elsewhere in more detail,
it is possible that oxidized phospholipids, and/or other oxi-
dized lipids in oxidized LDL, contribute importantly to the
inflammatory cascade in the lesions.7
We have no idea yet how long it will take to cause a
vulnerable plaque in humans to revert to a stable plaque, and
that would seem to be the most relevant datum. There may be
only poor correlation between measures of anatomic regres-
sion and risk of infarction. However, the fact that in some
trials the event rate in the experimental group has become
significantly lower within the first 6 months of lipid lowering
strongly suggests that even a relatively small degree of
anatomic regression and/or plaque stabilization is enough
to significantly reduce risk.
Recently, striking evidence of the reversibility of lesions
has been seen in mouse models. Desurmont and coworkers62
showed that the hypercholesterolemia in apolipoprotein
Enull mice crossed into immunodeficient (nude) mice can
be rapidly corrected by introducing the human apolipoprotein
E gene via an adenoviral vector. The plasma cholesterol level
returned to almost normal within a week or 2, from 400 down
to 100 mg/dL, and because no immune response occurred, it
stayed down for at least 100 days. Lesion size in the proximal
aorta at 17 weeks, which is when the adenoviral vector was
injected, was 105 m2; over the next 28 weeks, in the
controls (LacZ vector), it further increased 6-fold. However,
in the mice receiving the apolipoprotein E vector, lesion size
decreased by almost 90%. Moreover, there was a virtual
disappearance of foam cells and cholesterol from the lesions
and reendothelialization of the aorta.
Reis and colleagues63 have shown equally dramatic regres-
sion in mice. They devised a technique for transplanting a
lesion-containing thoracic aortic graft from a hypercholester-
olemic apolipoprotein Enull mouse into either a syngeneic
normocholesterolemic wild-type recipient or another synge-
neic hypercholesterolemic apolipoprotein Enull recipient.
This allowed the investigators to suddenly change the envi-
ronment in which the aortic lesion finds itself to whatever the
recipient blood offers. In this study, the donors had been on
a Western-type diet for a full 9 months, so they had advanced,
complicated lesions containing foam cells, intimal smooth
muscle cells, extracellular matrix, and lipid pools. Nine
weeks after transplantation into normocholesterolemic recip-
ients, atherosclerotic changes had all but disappeared; in
contrast, after 9 weeks in the hypercholesterolemic apoli-
poprotein Enull recipient, the lesions had increased further
in size.
Finally, we call attention again to an impressive series of
articles59 61,64 showing that returning cholesterol-fed rab-
bits to a chow dietand thus lowering their blood cholesterol
without pharmacological interventionmarkedly reduced
many proinflammatory processes associated with lesion
progression.
 Steinberg et al
Taken together, all of these findings suggest that the
inflammation associated with atherogenesis is not sufficient
in itself to cause further lesion progression or even to
maintain lesions at a steady state once the hypercholesterol-
emia has been fully corrected. In other words, many (or even
most) of the inflammatory processes in the advancing lesion
are downstream responses ultimately traceable to hyperlipid-
emia and its consequences. Consequently, early and aggres-
sive correction of hypercholesterolemia may be sufficient. On
the other hand, if hypolipidemic therapy is initiated at, say, 40
or 50 years of age, optimal intervention will no doubt also
require attention to inflammation, thrombosis, and hemody-
namic factors.
Implications for Management
Progress in this area of medicine has been rapid. As a result,
public health policies and guidelines for practitioners have
tended to lag behind. The time is ripe for a fresh look at the
issues, taking a longer-term view. At the top of the agenda
should be the issue of early treatment of hypercholesterol-
emia. We know the disease is already well on its way by 30
years of age, yet current guidelines do not take into account
the natural history of the disease. How shall we change our
approach? Lloyd-Jones and colleagues65 68 make a cogent
argument for using lifetime risk rather than short-term,
10-year risk as the arbiter of how intensive therapy should be.
Their analysis of data from the Framingham cohort shows
that for men 40 years of age with a total cholesterol level of
200 to 239 mg/dL, the 10-year risk for CHD is only 5%, but
the lifetime risk is 43%.
Eliminating age from risk prediction models includes both
pros and cons,69,70 but in many respects, it is an attractive way
to encourage earlier intervention in patients with high-risk
profiles. Other algorithms should be evaluated, taking into
account all the relevant risk factors and leading to interven-
tion at the appropriate level of intensity. Initiation of therapy
at least by 30 years of age would seem to be warranted in any
patient with a lifetime risk 40%.
Of course, children with familial hypercholesterolemia
should be started very early in life on statins, and other agents
if necessary, to lower their LDL to 50 mg/dL. Adults with
existing CHD or multiple risk factors also should strive to
lower their LDL to 50 mg/dL. In fact, on the basis of the
accumulated evidence reviewed above, it would be reason-
able to recommend that an ideal LDL cholesterol level
should be defined as 50 mg/dL. That goal is currently
attainable in many patients with the treatment regimens now
available, which include statins alone or in combination with
other hypolipidemic drugs, including bile acid sequestrants,
niacin, fibrates, and ezetimibe. In the future, new agents
should become available to help reach these lowered goals in
almost everyone.
The Ultimate Long-Term Solution
If indeed the low pre-Westernization CHD rate in Japan was,
as discussed above, due primarily to lifestyle differences (diet
and exercise), then our long-term goal should be to alter our
lifestyle accordingly, beginning in infancy or early childhood.
Is such a radical proposal totally impractical? It would, of
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Earlier Treatment of Hypercholesterolemia 675
course, take generations to achieve and would require an
all-out commitment of money and manpower to reeducate
and modify the behavior of the nation. Is that impossible? No.
We have already shown that even a frankly addictive behav-
ior like cigarette smoking can be overcome (eventually) with
the right combination of education, peer pressure, and legis-
lation. Would it be safe? Data are now available to show that
instituting a low-saturated-fat, low-cholesterol diet in infancy
(7 months) is perfectly safe without adverse effects on
growth, development, and sexual maturation.71,72
The importance of early intervention is becoming apparent
in another common chronic disease entity, type 2 diabetes
mellitus. Early treatment has been shown to prevent progres-
sion of prediabetes to frank clinical diabetes.7375 Interest-
ingly, intensive intervention on lifestyle factors (ie, diet and
exercise) was just as effective as or more effective than
intervention with drugs (metformin). It is now considered best
practice to anticipate the conversion of prediabetes (impaired
glucose tolerance) to frank diabetes mellitus and to forestall
that conversion by early intervention. In much the same way,
it should become best practice to anticipate the conversion of
the fatty streak to the fibrous plaque by treating hypercholes-
terolemia at a much earlier age.
The NIH has already committed itself to wars on obesity
and diabetes mellitus. The weapons for those wars educa-
tion and behavior modificationare the same as those
needed for a war on CHD. The overlaps are obvious. A
concerted national public health program might dramatically
reduce morbidity and mortality resulting from these 3 major
chronic diseases.
Summary
With the advent of the statins, enormous progress has been
made in the management of hypercholesterolemia. However,
some authorities point out, quite correctly, that statin treat-
ment reduces event rates by only 30% and suggest that
preventing the other 70% will require more than just control
of hypercholesterolemia (eg, adjunctive use of antiinflamma-
tory or immunologic interventions). This may discourage
clinicians from pressing on to do the best that can be done
with the interventional tools already at hand. This review has
summarized the evidence, drawn from a variety of sources,
that the results of the 5-year statin trials seriously underesti-
mate the ultimate potential of cholesterol-lowering therapy.
We suggest that this evidence mandates continuing and more
aggressive use of lipid-lowering regimens and, even more
important, intervention at an earlier stage in the development
of the atherosclerotic lesion.
Disclosures
Drs Witztum and Glass are on the Merck Speakers Bureau. Dr
Witztum is a consultant to AtheroGenics Inc. Dr Steinberg reports no
conflicts.
References
1. Steinberg D. The cholesterol controversy is over: why did it take so long?
Circulation. 1989;80:1070 1078.
2. Grundy SM. United States Cholesterol Guidelines 2001: expanded scope
of intensive low-density lipoprotein-lowering therapy. Am J Cardiol.
2001;88:23J27J.
676 Circulation August 5, 2008
3. Steinberg D. The Cholesterol Wars: The Cholesterol Skeptics vs the
Preponderance of Evidence. New York NY: Academic Press/Elsevier,
Inc; 2007.
4. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C,
Kirby A, Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of
cholesterol-lowering treatment: prospective meta-analysis of data from
90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:
12671278.
5. Libby P. The forgotten majority: unfinished business in cardiovascular
risk reduction. J Am Coll Cardiol. 2005;46:12251228.
6. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease.
N Engl J Med. 2005;352:16851695.
7. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001;104:
503516.
8. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis.
Circulation. 2002;105:11351143.
9. McGill HC Jr, McMahan CA. Starting earlier to prevent heart disease.
JAMA. 2003;290:2320 2322.
10. Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der
Graaf A, de Groot E, Wijburg FA, Kastelein JJ, Hutten BA. Statin
treatment in children with familial hypercholesterolemia: the younger, the
better. Circulation. 2007;116:664 668.
11. OKeefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal
low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiolog-
ically normal. J Am Coll Cardiol. 2004;43:21422146.
12. Brown MS, Goldstein JL. Biomedicine: lowering LDL: not only how low,
but how long? Science. 2006;311:17211723.
13. Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM.
Long-term follow-up of the West of Scotland Coronary Prevention Study.
N Engl J Med. 2007;357:14771486.
14. Domanski MJ. Primary prevention of coronary artery disease. N Engl
J Med. 2007;357:15431545.
15. Kimura N. Analysis of 10,000 postmortem examinations in Japan. In:
Keys A, White PD, eds. World Trends in Cardiology: Selected Papers
From Second World Congress of Cardiology. New York, NY: Hoeber-
Harper; 1956.
16. Gore I, Nakashima T, Imai T, White PD. Coronary atherosclerosis and
myocardial infarction in Kyushu, Japan, and Boston, Massachusetts.
Am J Cardiol. 1962;10:400 406.
17. Todd GF. Cigarette consumption per adult of each sex in various
countries. J Epidemiol Community Health. 1978;32:289 293.
18. Stehle G, Hinohara S, Cremer P, Feng Z, Bernhardt R, Goto Y, Seidel D,
Heene DL, Schettler G. Differences in the risk factor patterns for
coronary heart disease in China, Japan, and Germany. Klin Wochenschr.
1991;69:629 632.
19. Prevalence of small vessel and large vessel disease in diabetic patients
from 14 centres: the World Health Organisation Multinational Study of
Vascular Disease in Diabetics: Diabetes Drafting Group. Diabetologia.
1985;28(suppl):615 640.
20. Marmot MG, Syme SL, Kagan A, Kato H, Cohen JB, Belsky J. Epide-
miologic studies of coronary heart disease and stroke in Japanese men
living in Japan, Hawaii and California: prevalence of coronary and hyper-
tensive heart disease and associated risk factors. Am J Epidemiol. 1975;
102:514 525.
21. Robertson TL, Kato H, Rhoads GG, Kagan A, Marmot M, Syme SL,
Gordon T, Worth RM, Belsky JL, Dock DS, Miyanishi M, Kawamoto S.
Epidemiologic studies of coronary heart disease and stroke in Japanese
men living in Japan, Hawaii and California: incidence of myocardial
infarction and death from coronary heart disease. Am J Cardiol. 1977;
39:239 243.
22. Schwartz MJ, Rosensweig B, Toor M, Lewitus Z. Lipid metabolism and
arteriosclerotic heart disease in Israelis of Bedouin, Yemenite and
European origin. Am J Cardiol. 1963;12:157168.
23. Keys A. Diet and the epidemiology of coronary heart disease. JAMA.
1957;164:19121919.
24. Enos WF, Holmes RH, Beyer J. Coronary disease among United States
soldiers killed in action in Korea: preliminary report. JAMA. 1953;152:
1090 1093.
25. Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE, McCarthy PM,
Young JB, Nissen SE. High prevalence of coronary atherosclerosis in
asymptomatic teenagers and young adults: evidence from intravascular
ultrasound. Circulation. 2001;103:27052710.
26. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R,
Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate
Downloaded from http://circ.ahajournals.org/ by guest on December 22, 2013
lipid lowering with statins after acute coronary syndromes. N Engl J Med.
2004;350:14951504.
27. Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM,
Jackson G, Braunwald E. Early and late benefits of high-dose atorvastatin
in patients with acute coronary syndromes: results from the PROVE
IT-TIMI 22 trial. J Am Coll Cardiol. 2005;46:14051401.
28. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S,
Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of lowering
LDL cholesterol substantially below currently recommended levels in
patients with coronary heart disease and diabetes: the Treating to New
Targets (TNT) study. Diabetes Care. 2006;29:1220 1226.
29. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald
E. Can low-density lipoprotein be too low? The safety and efficacy of
achieving very low low-density lipoprotein with intensive statin therapy:
a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46:14111416.
30. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA,
Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN.
Effect of intensive compared with moderate lipid-lowering therapy on
progression of coronary atherosclerosis: a randomized controlled trial.
JAMA. 2004;291:10711080.
31. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC,
Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK. Intensive
lipid lowering with atorvastatin in patients with stable coronary disease.
N Engl J Med. 2005;352:14251435.
32. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hun-
ninghake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of
recent clinical trials for the National Cholesterol Education Program
Adult Treatment Panel III guidelines. Circulation. 2004;110:227239.
33. Executive Summary of the Third Report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel
III). JAMA. 2001;285:2486 2497.
34. Leeper NJ, Ardehali R, deGoma EM, Heidenreich PA. Statin use in
patients with extremely low low-density lipoprotein levels is associated
with improved survival. Circulation. 2007;116:613 618.
35. McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE,
McGovern ME. Comparative effects on lipid levels of combination
therapy with a statin and extended-release niacin or ezetimibe versus a
statin alone (the COMPELL study). Atherosclerosis. 2007;192:432 437.
36. Bradford RH, Shear CL, Chremos AN, Dujovne CA, Franklin FA, Grillo
RB, Higgins J, Langendorfer A, Nash DT, Pool JL. Expanded Clinical
Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and
safety follow-up. Am J Cardiol. 1994;74:667 673.
37. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol
homeostasis. Science. 1986;232:34 47.
38. Mills GL, Taylaur CE. The distribution and composition of serum
lipoproteins in eighteen animals. Comp Biochem Physiol B. 1971;40:
489 501.
39. Davis PA, Forte TM. Neonatal umbilical cord blood lipoproteins: iso-
lation and characterization of intermediate density and low density
lipoproteins. Arteriosclerosis. 1982;2:37 43.
40. Steinberg D, Grundy SM, Mok HY, Turner JD, Weinstein DB, Brown
WV, Albers JJ. Metabolic studies in an unusual case of asymptomatic
familial hypobetalipoproteinemia with hypoalphalipoproteinemia and
fasting chylomicronemia. J Clin Invest. 1979;64:292301.
41. Young SG, Bertics SJ, Curtiss LK, Dubois BW, Witztum JL. Genetic
analysis of a kindred with familial hypobetalipoproteinemia: evidence for
two separate gene defects: one associated with an abnormal apoli-
poprotein B species, apolipoprotein B-37; and a second associated with
low plasma concentrations of apolipoprotein B-100. J Clin Invest. 1987;
79:18421851.
42. Scandinavian Simvastatin Survival Study Group. Randomised trial of
cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:
13831389.
43. MRC/BHF Heart Protection Study of cholesterol lowering with simva-
statin in 20,536 high-risk individuals: a randomised placebo-controlled
trial. Lancet. 2002;360:722.
44. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW,
McKillop JH, Packard CJ. Prevention of coronary heart disease with
pravastatin in men with hypercholesterolemia: West of Scotland
Coronary Prevention Study Group. N Engl J Med. 1995;333:13011307.
45. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA,
Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention
of acute coronary events with lovastatin in men and women with average
 Steinberg et al
cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas
Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:
16151622.
46. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,
Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E.
The effect of pravastatin on coronary events after myocardial infarction in
patients with average cholesterol levels: Cholesterol and Recurrent
Events Trial Investigators. N Engl J Med. 1996;335:10011009.
47. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE,
Wattigney WA. Association between multiple cardiovascular risk factors
and atherosclerosis in children and young adults: the Bogalusa Heart
Study. N Engl J Med. 1998;338:1650 1656.
48. Malcom GT, Oalmann MC, Strong JP. Risk factors for atherosclerosis in
young subjects: the PDAY Study: Pathobiological Determinants of Ath-
erosclerosis in Youth. Ann N Y Acad Sci. 1997;817:179 188.
49. McMahan CA, McGill HC, Gidding SS, Malcom GT, Newman WP,
Tracy RE, Strong JP. PDAY risk score predicts advanced coronary artery
atherosclerosis in middle-aged persons as well as youth. Atherosclerosis.
2007;190:370 377.
50. Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Buller
HR, Sijbrands EJ, Kastelein JJ. Efficacy and safety of statin therapy in
children with familial hypercholesterolemia: a randomized controlled
trial. JAMA. 2004;292:331337.
51. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M,
Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L,
Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc
G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG,
Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholes-
terolemia. Nat Genet. 2003;34:154 156.
52. Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL. Novel
putative SREBP and LXR target genes identified by microarray analysis
in liver of cholesterol-fed mice. J Lipid Res. 2003;44:2109 2119.
53. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs
HH. Low LDL cholesterol in individuals of African descent resulting
from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:
161165.
54. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations
in PCSK9, low LDL, and protection against coronary heart disease.
N Engl J Med. 2006;354:1264 1272.
55. McPherson R, Kavaslar N. Statins for primary prevention of coronary
artery disease. Lancet. 2007;369:1078.
56. Myocardial Infarction Genetics Consortium. Proprotein convertase sub-
tilisin/kexin type 9 (PCSK9)missense variant is reproducibly associated
with early-onset myocardial infarction in 1500 cases and 1500 controls.
Circulation. 2007;116(suppl):II 806. Abstract.
57. Armstrong ML, Warner ED, Connor WE. Regression of coronary ather-
omatosis in rhesus monkeys. Circ Res. 1970;27:59 67.
58. Armstrong ML, Megan MB. Lipid depletion in atheromatous coronary
arteries in rhesus monkeys after regression diets. Circ Res. 1972;30:
675 680.
59. Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, Brinckerhoff CE,
Sukhova GK, Libby P. Lipid lowering by diet reduces matrix metallo-
proteinase activity and increases collagen content of rabbit atheroma: a
potential mechanism of lesion stabilization. Circulation. 1998;97:
24332444.
60. Aikawa M, Libby P. Lipid lowering reduces proteolytic and pro-
thrombotic potential in rabbit atheroma. Ann N Y Acad Sci. 2000;902:
140 152.
Downloaded from http://circ.ahajournals.org/ by guest on December 22, 2013
Earlier Treatment of Hypercholesterolemia 677
61. Aikawa M, Sugiyama S, Hill CC, Voglic SJ, Rabkin E, Fukumoto Y,
Schoen FJ, Witztum JL, Libby P. Lipid lowering reduces oxidative stress
and endothelial cell activation in rabbit atheroma. Circulation. 2002;106:
1390 1396.
62. Desurmont C, Caillaud JM, Emmanuel F, Benoit P, Fruchart JC, Castro
G, Branellec D, Heard JM, Duverger N. Complete atherosclerosis
regression after human ApoE gene transfer in ApoE-deficient/nude mice.
Arterioscler Thromb Vasc Biol. 2000;20:435 442.
63. Reis ED, Li J, Fayad ZA, Rong JX, Hansoty D, Aguinaldo JG, Fallon JT,
Fisher EA. Dramatic remodeling of advanced atherosclerotic plaques of
the apolipoprotein E-deficient mouse in a novel transplantation model.
J Vasc Surg. 2001;34:541547.
64. Aikawa M, Voglic SJ, Sugiyama S, Rabkin E, Taubman MB, Fallon JT,
Libby P. Dietary lipid lowering reduces tissue factor expression in rabbit
atheroma. Circulation. 1999;100:12151222.
65. Lloyd-Jones DM, Wilson PW, Larson MG, Beiser A, Leip EP,
DAgostino RB, Levy D. Framingham risk score and prediction of
lifetime risk for coronary heart disease. Am J Cardiol. 2004;94:20 24.
66. Lloyd-Jones DM, Leip EP, Larson MG, DAgostino RB, Beiser A,
Wilson PW, Wolf PA, Levy D. Prediction of lifetime risk for cardiovas-
cular disease by risk factor burden at 50 years of age. Circulation.
2006;113:791798.
67. Lloyd-Jones DM. Short-term versus long-term risk for coronary artery
disease: implications for lipid guidelines. Curr Opin Lipidol. 2006;17:
619 625.
68. Lloyd-Jones DM, Wilson PW, Larson MG, Leip E, Beiser A, DAgostino
RB, Cleeman JI, Levy D. Lifetime risk of coronary heart disease by
cholesterol levels at selected ages. Arch Intern Med. 2003;163:
1966 1972.
69. Vasan RS, DAgostino RB Sr. Age and time need not and should not be
eliminated from the coronary risk prediction models. Circulation. 2005;
111:542545.
70. Ridker PM, Cook N. Should age and time be eliminated from cardiovas-
cular risk prediction models? Rationale for the creation of a new national
risk detection program. Circulation. 2005;111:657 658.
71. Niinikoski H, Lagstrom H, Jokinen E, Siltala M, Ronnemaa T, Viikari J,
Raitakari OT, Jula A, Marniemi J, Nanto-Salonen K, Simell O. Impact of
repeated dietary counseling between infancy and 14 years of age on
dietary intakes and serum lipids and lipoproteins: the STRIP Study.
Circulation. 2007;116:10321040.
72. Daniels SR. Diet and primordial prevention of cardiovascular disease in
children and adolescents. Circulation. 2007;116:973974.
73. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-
Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas
M, Salminen V, Uusitupa M. Prevention of type 2 diabetes mellitus by
changes in lifestyle among subjects with impaired glucose tolerance.
N Engl J Med. 2001;344:13431350.
74. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM,
Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes
with lifestyle intervention or metformin. N Engl J Med. 2002;346:
393 403.
75. Haffner S. Diabetes and the metabolic syndrome: when is it best to
intervene to prevent? Atheroscler Suppl. 2006;7:310.
KEY WORDS: atherosclerosis hypercholesterolemia inflammation
myocardial infarction prevention