Ben-Yehuda, Ori

DeMaria, Anthony N.

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Low LDL-C Levels and Cancer Reassuring But Still Not Definitive⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

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Journal of the American College of Cardiology Vol. 52, No. 14, 2008
© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2008.08.001EDITORIAL COMMENT
ow LDL-C Levels and Cancer
eassuring But Still Not Definitive*
ri Ben-Yehuda, MD, FACC,
nthony N. DeMaria, MD, MACC
an Diego, California
therosclerosis and its complications, coronary heart
isease, stroke, and peripheral arterial disease, remain the
eading cause of death and are increasing in incidence in
he developing world (1). Treatment of dyslipidemia,
articularly lowering of low-density lipoprotein choles-
erol (LDL-C), is currently the cornerstone in the
revention and treatment of atherosclerosis. Not surpris-
ngly, therefore, millions of patients worldwide are being
reated with lipid-lowering agents, particularly statins.
nd while the beneficial effects of LDL-C lowering have
een validated in multiple clinical trials, there remains
ncertainty regarding LDL-C targets. Moreover, know-
ng whether adverse noncardiovascular events are associ-
ted with low LDL-C levels is of great clinical impor-
ance as physicians and patients balance risk versus
enefit.
See pages 1141 and 1148
In this issue of the Journal, Alsheikh-Ali et al. (2)
resent a meta-regression analysis of data from 15 ran-
omized clinical trials. They conclude that, while an
nverse association between on-treatment LDL-C and
ncident cancer occurs, there was no evidence that statins
hemselves increased the risk of cancer. This analysis was
rompted by an earlier study published in the Journal in
hich the same investigators identified evidence of in-
reased incident cancers in relation to lower LDL-C
evels achieved in various statin trials (3). In an accompa-
ying editorial, Dr. Daniel Steinberg (4) concludes that
ndeed statin treatment does not cause cancer. Among
xplanations for the LDL-C level’s association with
Editorials published in the Journal of the American College of Cardiology reflect the
iews of the authors and do not necessarily represent the views of JACC or the
merican College of Cardiology.
From the Division of Cardiovascular Medicine, University of California, San Diego
edical Center, San Diego, California. Dr. Ben-Yehuda is a member of the Speakers’s
ureau and has served as an adviser to Schering-Plough Pharmaceuticals and has
eceived research grants from Merck and Co.ncident cancer, he emphasizes the possible role of
ubclinical cancers as well as the confounding effect of
ther diseases that may lower LDL-C as well as increase
isk for cancers.
Is the issue completely resolved? As this article and
ccompanying editorial were going to press, the prelim-
nary results of the SEAS (Effects of Simvastatin and
zetimibe on Clinical Outcomes in Patients with Aortic
tenosis) study were released (5). In this placebo-
ontrolled study of patients with aortic stenosis, LDL-C
as reduced by 61% to a mean of 52 mg/dl in the active
rm (6). The study failed to meet its primary end point in
educing major cardiovascular events (atherosclerotic dis-
ase events were reduced significantly, while aortic valve
isease events were not reduced). Of concern was the
nding that cancer rates were increased significantly in
he active arm of the study, with 102 cases versus 67
ases in the control arm. The press release for the study
as accompanied by an analysis from 2 other ongoing
arge trials with simvastatin/ezetimibe combination
IMPROVE-IT [IMProved Reduction of Outcomes:
ytorin Efficacy International Trial] and SHARP [Study
f Heart and Renal Protection]), which in a pooled
nalysis showed no excess of cancers (5). Several impor-
ant limitations of this analysis need to be highlighted: 1)
uration of treatment experience in these ongoing trials is
ignificantly shorter than in the SEAS study; 2) while
HARP is a placebo-controlled trial, the larger
MPROVE-IT study is a comparison of 2 active arms
simvastatin/ezetimibe vs. simvastatin alone); and 3)
DL-C levels (both starting and on treatment) for these
rials were not reported—entry criteria for the IMPROVE-IT
tudy, however, mandate relatively low starting LDL-C
evels (125 mg/dl for treatment naïve subjects) and both
reatment arms are expected to have low LDL-C levels,
ossibly obscuring any potential adverse effect of low
DL-C levels (7).
So while statin treatment in itself appears not to
ncrease risk of cancer, the issue of a possible link
etween very low LDL-C levels and cancer has not been
ully resolved. If indeed background disease (whether
ubclinical cancers or other comorbidities that lower
holesterol and also increase cancer risk) is to account for
he link, one would expect a lower LDL-C to be apparent
n entry into the study. Moreover, statins result in a very
rompt reduction in cholesterol and LDL-C levels. As
rials routinely monitor response to therapy in addition to
ollecting clinical events, the effect of drug-induced
DL-C reductions versus background low LDL-C level
ould be differentiated on a patient-level analysis. Indeed,
he major limitation in both the original article by
lsheikh-Ali et al. (3) and the present, more complete
nalysis (2), is the lack of patient-level data. As there is a
pectrum of LDL-C levels within each trial (both due to
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1151JACC Vol. 52, No. 14, 2008 Ben-Yehuda and DeMaria
September 30, 2008:1150–1 Editorial Commentifferent baseline levels as well as differing responses to
he lipid lowering agents), focusing only on mean levels
ay obscure an important link that can only be ascer-
ained by analyzing patient-level data.
The reporting of cancer rates in many of the clinical trials
as been incomplete. For example, the main Treat to New
argets publication reported a statistically insignificant
ncrease in cancer deaths (85 cases vs. 75 cases) in the
ntensive 80-mg atorvastatin arm versus the 10-mg arm, but
id not report overall cancer incidence (8). Given the
mportance of the topic, it is paramount that the Food and
rug Administration and the pharmaceutical industry
romptly analyze and report the cancer incidence in the
arious trials with a patient-level analysis.
When the initial report by Alsheikh-Ali et al. (3) was
ublished, we accompanied it by an editorial titled “Low-
ensity Lipoprotein Reduction in Cancer: Not Definitive
ut Provocative” (9). We highlighted the wisdom of present
uidelines that emphasize a link between baseline cardio-
ascular risk and LDL-C goals and cautioned that the
nalysis needed to be viewed as hypothesis generating.
imilarly, while reassured by their present analysis (2), we
till believe that further study is mandated. The findings
rom the SEAS study, while not definitive, support this
eed. We also reaffirm our belief that the present guidelines
dequately balance the clear benefit of LDL-C lowering
ith potential risks. Keprint requests and correspondence: Dr. Anthony N. De-
aria, Editor-in-Chief, Journal of the American College of Cardi-
logy, 3655 Nobel Drive, Suite 400, San Diego, California 92122.
-mail: ademaria@acc.org.
EFERENCES
. Callow AD. Cardiovascular disease 2005—the global picture. Vascular
Pharmacology 2006;45:302–7.
. Alsheikh-Ali AA, Trikalinos TA, Kent DM, Karas RH. Statins,
low-density lipoprotein cholesterol, and risk of cancer. J Am Coll
Cardiol 2008;52:1141–7.
. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the
magnitude of lipid lowering on risk of elevated liver enzymes, rhabdo-
myolysis, and cancer: insights from large randomized statin trials. J Am
Coll Cardiol 2007;50:409–18.
. Steinberg D. Statin treatment does not cause cancer. J Am Coll Cardiol
2008;52:1148–9.
. Independent Analyses of the SEAS, SHARP, and IMPROVE-IT
Studies of Ezetimibe. Available at: http://www.ctsu.ox.ac.uk/news/
index_html. Accessed July 29, 2008.
. SEAS Press Conference. Available at: http://clients.mediaondemand.
net/pedersen/. Accessed July 29, 2008.
. IMPROVE-IT: Examining Outcomes in Subjects With Acute Coro-
nary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study
P04103). Available at: http://clinicaltrials.gov/show/NCT00202878.
Accessed July 29, 2008.
. La Rosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering
with atorvastatin in patients with stable coronary disease. N Engl J Med
2005;352:14.
. DeMaria AN, Ben-Yehuda O. Low-density lipoprotein reduction and
cancer: not definitive but provocative. J Am Coll Cardiol 2007;50:
421–2.ey Words: statin y cholesterol y cancer y ezetimibe y atherosclerosis.


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Low LDL-C Levels and Cancer Reassuring But Still Not Definitive⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

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