JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 9, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.04.076
EDITORIAL COMMENT
Is Lp(a) Ready for Prime Time?* Stephen J. Nicholls, MBBS, PHD,yz Alex Brown, MBBS, PHDyx
D
espite the established benefits of random-
challenge, given inconsistencies in reports of protec-
ized controlled trials in the primary and
tion from heart disease, in terms of both association
secondary prevention settings, atheroscle-
with risk (4) and the lack of efficacy of HDL-C–raising
rotic cardiovascular disease continues to present a
therapies (5,6). Increasing evidence implicates an
major public health challenge throughout the world.
independent role for measurements of triglycerides
Beyond the critical, often overlooked importance of
(7), as well as remnant lipoprotein particles (8), in
lifestyle measures, new efforts to improve disease
risk prediction. However, the demonstration that
prevention will require more effective approaches to
lowering the levels of these substances translates to
tailor risk assessment and subsequently to modify
clinical benefit remains to be established.
that risk. The successful targeting of low-density
In parallel, lipoprotein (a), abbreviated Lp(a), con-
lipoprotein cholesterol (LDL-C) represents a model
tinues to receive considerable attention with regard
on which to base these future developments. The
to its potential role in promoting atherosclerosis and
findings that LDL-C levels are directly associated
its role in risk reduction strategies. Lp(a) has unique
with cardiovascular risk and that lowering its levels
structural properties that combine stimulatory effects
results in fewer clinical events underscore the impor-
on atherogenic and thrombotic pathways that un-
tance of LDL-C in strategies designed to prevent car-
derlie the pathogenesis of acute ischemic events (9).
diovascular disease (1).
SEE PAGE 851
However, the findings that many persons judged to be not at high risk by standard risk prediction models
In this issue of the Journal, Willeit et al. (10) report
experience clinical events (2) and that adverse
findings of their investigation on the capability of
cardiovascular outcomes continue to be observed in
Lp(a) levels to discriminate cardiovascular risk over a
patients who undergo intensive modification of
15-year
traditional risk factors (3) suggest an urgent need to
community-based study of 826 men and women who
develop additional approaches to risk stratification.
were 45 to 84 years old, a direct relationship was
Although ongoing studies are evaluating LDL-C–
observed between Lp(a) levels and the subsequent
lowering strategies in addition to statins, attention
incidence of major adverse cardiovascular events.
period
in
the
Bruneck
Study.
In
this
also has turned to a range of other lipid factors
This finding supports a growing body of evidence
implicated in atherosclerotic disease. High-density
linking Lp(a) levels and cardiovascular risk. Most
lipoprotein cholesterol (HDL-C) continues to be a
importantly, however, the current analysis provides compelling evidence to support a potential role of Lp(a) in reclassification of patients previously deter-
*Editorials published in the Journal of the American College of Cardiology
mined to be at intermediate cardiovascular risk on the
reflect the views of the authors and do not necessarily represent the
basis of traditional algorithms. In fact, nearly 2 in 5 of
views of JACC or the American College of Cardiology.
such patients underwent restratification to either
From the ySouth Australian Health and Medical Research Institute,
lower or higher cardiovascular risk settings.
University of South Australia, Adelaide, Australia; zDiscipline of Medicine, University of Adelaide, Adelaide, Australia; and the xSchool of
Although these observations are of potential in-
Population Health, University of South Australia, Adelaide, Australia.
terest in expanding the clinical use of Lp(a), certain
Dr. Nicholls has received research support from AstraZeneca, Eli Lilly,
issues remain unresolved. Do such findings influence
Cerenis, Anthera, Omthera, Roche, Novartis, Resverlogix, InfraReDx,
the integration of Lp(a) testing into risk prediction
Amgen, and LipoScience; and is a consultant for AstraZeneca, Boehringer Ingelheim, CSL Behring, Merck, Takeda, Roche, Omthera, Novartis,
algorithms? In general, the use of this testing is not
Amgen, Sanofi-Aventis, and Eli Lilly. Dr. Brown has reported that he has
widespread; it tends to be confined to subsets of
no relationships relevant to the contents of this paper to disclose.
patients, including those with premature coronary
862
Nicholls and Brown
JACC VOL. 64, NO. 9, 2014 SEPTEMBER 2, 2014:861–2
Is Lp(a) Ready for Prime Time?
disease in the absence of any major cardiovascular
lower Lp(a) levels and in turn reduce event rates
risk factor. Whether systematic screening of Lp(a) will
is attractive. Disappointingly, estrogen and nico-
be of clinical benefit will ultimately require validation
tinic acid both lower Lp(a), among their other
that it changes practice and clinical outcomes in a
actions, yet they did not reduce cardiovascular
cost-effective manner. Such studies have not been
event rates in clinical trials. Experimental therapies
performed. Similarly, the relative utility of serial
with, for example, cholesteryl ester transfer pro-
evaluation of Lp(a) is untested. Increasing evidence
tein (CETP) and proprotein convertase subtilisin
has highlighted the potential differences between
kexin type 9 (PCSK9) inhibitors lower Lp(a), but
Lp(a) isoforms with regard to their relationship with
any potential
cardiovascular risk (9). Of particular interest, no such
from other lipid effects. Whether a more selective
association was demonstrated in the current analysis
Lp(a)-lowering strategy will prove protective remains
beyond the predictive capability of Lp(a) levels.
to be tested.
clinical
benefit
is
likely
derived
Ultimately, we need to ask how such measurements
This body of evidence supports a potential role
will change clinical practice. In an ever-changing
for Lp(a) as both a risk marker and a target for
world of lipid guidelines, some countries will use
therapeutic lowering. Whether Lp(a) will identify
Lp(a) to identify higher-risk patients, whereas other
the patient with modifiable cardiovascular risk is
countries, wanting to adhere more closely to evidence
unknown. The field is in great need of clinical
from randomized clinical trials, will find an absence
trials to determine the optimal use of Lp(a). As a
of data. Most physicians who routinely measure
result, the journey of Lp(a) toward routine use
Lp(a) levels will use such results for triage of patients
continues.
to more intensive use of established preventive therapies. The finding that Lp(a) levels tend to be
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
less predictive of cardiovascular outcomes in patients
Stephen Nicholls, South Australian Health and Medical
with very low LDL-C levels supports, but does
Research Institute, P.O. Box 11060, Adelaide, South
not validate, the use of more intensive statin therapy
Australia, 5001, Australia. E-mail: stephen.nicholls@
(11). The concept of developing agents that specifically
sahmri.com.
REFERENCES 1. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81. 2. Lloyd-Jones DM. Cardiovascular risk prediction: basic concepts, current status, and future directions. Circulation 2010;121:1768–77. 3. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol 2005;46:1225–8. 4. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 2012;380:572–80. 5. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent
acute coronary syndrome. N Engl J Med 2012;367: 2089–99. 6. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–67. 7. Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345–61. 8. Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128: 1298–309.
9. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31: 2844–53. 10. Willeit P, Kiechl S, Kronenberg F, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 2014;64:851–60. 11. Nicholls SJ, Tang WH, Scoffone H, et al. Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy. J Lipid Res 2010;51:3055–61.
KEY WORDS atherosclerosis, autoantibodies, lipoproteins, oxidation, oxidation-specific epitopes, oxidized phospholipids
VOL. 64, NO. 9, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.04.076
EDITORIAL COMMENT
Is Lp(a) Ready for Prime Time?* Stephen J. Nicholls, MBBS, PHD,yz Alex Brown, MBBS, PHDyx
D
espite the established benefits of random-
challenge, given inconsistencies in reports of protec-
ized controlled trials in the primary and
tion from heart disease, in terms of both association
secondary prevention settings, atheroscle-
with risk (4) and the lack of efficacy of HDL-C–raising
rotic cardiovascular disease continues to present a
therapies (5,6). Increasing evidence implicates an
major public health challenge throughout the world.
independent role for measurements of triglycerides
Beyond the critical, often overlooked importance of
(7), as well as remnant lipoprotein particles (8), in
lifestyle measures, new efforts to improve disease
risk prediction. However, the demonstration that
prevention will require more effective approaches to
lowering the levels of these substances translates to
tailor risk assessment and subsequently to modify
clinical benefit remains to be established.
that risk. The successful targeting of low-density
In parallel, lipoprotein (a), abbreviated Lp(a), con-
lipoprotein cholesterol (LDL-C) represents a model
tinues to receive considerable attention with regard
on which to base these future developments. The
to its potential role in promoting atherosclerosis and
findings that LDL-C levels are directly associated
its role in risk reduction strategies. Lp(a) has unique
with cardiovascular risk and that lowering its levels
structural properties that combine stimulatory effects
results in fewer clinical events underscore the impor-
on atherogenic and thrombotic pathways that un-
tance of LDL-C in strategies designed to prevent car-
derlie the pathogenesis of acute ischemic events (9).
diovascular disease (1).
SEE PAGE 851
However, the findings that many persons judged to be not at high risk by standard risk prediction models
In this issue of the Journal, Willeit et al. (10) report
experience clinical events (2) and that adverse
findings of their investigation on the capability of
cardiovascular outcomes continue to be observed in
Lp(a) levels to discriminate cardiovascular risk over a
patients who undergo intensive modification of
15-year
traditional risk factors (3) suggest an urgent need to
community-based study of 826 men and women who
develop additional approaches to risk stratification.
were 45 to 84 years old, a direct relationship was
Although ongoing studies are evaluating LDL-C–
observed between Lp(a) levels and the subsequent
lowering strategies in addition to statins, attention
incidence of major adverse cardiovascular events.
period
in
the
Bruneck
Study.
In
this
also has turned to a range of other lipid factors
This finding supports a growing body of evidence
implicated in atherosclerotic disease. High-density
linking Lp(a) levels and cardiovascular risk. Most
lipoprotein cholesterol (HDL-C) continues to be a
importantly, however, the current analysis provides compelling evidence to support a potential role of Lp(a) in reclassification of patients previously deter-
*Editorials published in the Journal of the American College of Cardiology
mined to be at intermediate cardiovascular risk on the
reflect the views of the authors and do not necessarily represent the
basis of traditional algorithms. In fact, nearly 2 in 5 of
views of JACC or the American College of Cardiology.
such patients underwent restratification to either
From the ySouth Australian Health and Medical Research Institute,
lower or higher cardiovascular risk settings.
University of South Australia, Adelaide, Australia; zDiscipline of Medicine, University of Adelaide, Adelaide, Australia; and the xSchool of
Although these observations are of potential in-
Population Health, University of South Australia, Adelaide, Australia.
terest in expanding the clinical use of Lp(a), certain
Dr. Nicholls has received research support from AstraZeneca, Eli Lilly,
issues remain unresolved. Do such findings influence
Cerenis, Anthera, Omthera, Roche, Novartis, Resverlogix, InfraReDx,
the integration of Lp(a) testing into risk prediction
Amgen, and LipoScience; and is a consultant for AstraZeneca, Boehringer Ingelheim, CSL Behring, Merck, Takeda, Roche, Omthera, Novartis,
algorithms? In general, the use of this testing is not
Amgen, Sanofi-Aventis, and Eli Lilly. Dr. Brown has reported that he has
widespread; it tends to be confined to subsets of
no relationships relevant to the contents of this paper to disclose.
patients, including those with premature coronary
862
Nicholls and Brown
JACC VOL. 64, NO. 9, 2014 SEPTEMBER 2, 2014:861–2
Is Lp(a) Ready for Prime Time?
disease in the absence of any major cardiovascular
lower Lp(a) levels and in turn reduce event rates
risk factor. Whether systematic screening of Lp(a) will
is attractive. Disappointingly, estrogen and nico-
be of clinical benefit will ultimately require validation
tinic acid both lower Lp(a), among their other
that it changes practice and clinical outcomes in a
actions, yet they did not reduce cardiovascular
cost-effective manner. Such studies have not been
event rates in clinical trials. Experimental therapies
performed. Similarly, the relative utility of serial
with, for example, cholesteryl ester transfer pro-
evaluation of Lp(a) is untested. Increasing evidence
tein (CETP) and proprotein convertase subtilisin
has highlighted the potential differences between
kexin type 9 (PCSK9) inhibitors lower Lp(a), but
Lp(a) isoforms with regard to their relationship with
any potential
cardiovascular risk (9). Of particular interest, no such
from other lipid effects. Whether a more selective
association was demonstrated in the current analysis
Lp(a)-lowering strategy will prove protective remains
beyond the predictive capability of Lp(a) levels.
to be tested.
clinical
benefit
is
likely
derived
Ultimately, we need to ask how such measurements
This body of evidence supports a potential role
will change clinical practice. In an ever-changing
for Lp(a) as both a risk marker and a target for
world of lipid guidelines, some countries will use
therapeutic lowering. Whether Lp(a) will identify
Lp(a) to identify higher-risk patients, whereas other
the patient with modifiable cardiovascular risk is
countries, wanting to adhere more closely to evidence
unknown. The field is in great need of clinical
from randomized clinical trials, will find an absence
trials to determine the optimal use of Lp(a). As a
of data. Most physicians who routinely measure
result, the journey of Lp(a) toward routine use
Lp(a) levels will use such results for triage of patients
continues.
to more intensive use of established preventive therapies. The finding that Lp(a) levels tend to be
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
less predictive of cardiovascular outcomes in patients
Stephen Nicholls, South Australian Health and Medical
with very low LDL-C levels supports, but does
Research Institute, P.O. Box 11060, Adelaide, South
not validate, the use of more intensive statin therapy
Australia, 5001, Australia. E-mail: stephen.nicholls@
(11). The concept of developing agents that specifically
sahmri.com.
REFERENCES 1. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81. 2. Lloyd-Jones DM. Cardiovascular risk prediction: basic concepts, current status, and future directions. Circulation 2010;121:1768–77. 3. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol 2005;46:1225–8. 4. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 2012;380:572–80. 5. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent
acute coronary syndrome. N Engl J Med 2012;367: 2089–99. 6. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–67. 7. Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345–61. 8. Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128: 1298–309.
9. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31: 2844–53. 10. Willeit P, Kiechl S, Kronenberg F, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 2014;64:851–60. 11. Nicholls SJ, Tang WH, Scoffone H, et al. Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy. J Lipid Res 2010;51:3055–61.
KEY WORDS atherosclerosis, autoantibodies, lipoproteins, oxidation, oxidation-specific epitopes, oxidized phospholipids
