The relationship between Lp(a) and CVD outcomes: a systematic review
Forbes et al. Lipids in Health and Disease
The relationship between Lp(a) and CVD outcomes: a systematic review
Carol A. Forbes 0
Ruben G. W. Quek 2
Sohan Deshpande 0
Gill Worthy 0
Robert Wolff 0
Lisa Stirk 0
Jos Kleijnen 1
Shravanthi R. Gandra 2
Stephen Djedjos 2
Nathan D. Wong 3
0 Kleijnen Systematic Reviews Ltd , Unit 6, Escrick Business Park, Riccall Road, Escrick, York YO19 6FD , UK
1 School for Public Health and Primary Care, Maastricht University , Maastricht , The Netherlands
2 Amgen Inc , One Amgen Center Drive, Thousand Oaks, CA 91320-1799 , USA
3 University of California, Heart Disease Prevention Program, C240 Medical Sciences, University of California , Mail Code: 4079, Irvine, CA 92697 , USA
Robust associations between lipoprotein(a) [Lp(a)] and CVD outcomes among general populations have been published in previous studies. However, associations in high risk primary prevention and secondary prevention populations are less well defined. In order to investigate this further, a systematic review was performed including prospective studies, which assessed the relationship between Lp(a) and CVD outcomes using multivariable analyses. Additional information was gathered on Lp(a) assays, multivariable modelling and population characteristics. Literature searches from inception up to December 2015 retrieved 2850 records. From these 60 studies were included. Across 39 primary prevention studies in the general population (hazard ratios ranged from 1.16 to 2.97) and seven high risk primary prevention studies (hazard ratios ranged from 1.01 to 3.7), there was evidence of a statistically significant relationship between increased Lp(a) and an increased risk of future CVD. Results in 14 studies of secondary prevention populations were also suggestive of a modest statistically significant relationship (hazard ratios ranged from 0.75 to 3.7). Therefore current evidence would suggest that increased Lp(a) levels are associated with modest increases in the risk of future CVD events in both general and higher risk populations. However, further studies are required to confirm these findings.
Atherosclerosis; Epidemiology; Lipids; Lipoprotein; Cardiovascular risk
Background
Cardiovascular disease (CVD) is a leading cause of death
and disability [
1, 2
]. Elevated levels of low-density
lipoprotein cholesterol (LDL-C) are a major contributor to
atherosclerosis leading to subsequent CVD events.
Numerous clinical trials of lipid lowering drugs have found that
reducing LDL-C levels substantially reduces the risk of CVD
[
3–5
] suggesting a strong direct relationship between
plasma LDL-C levels and CVD outcomes [
6, 7
]. Many
people, however, still have residual CVD risk and suffer
from CVD events despite significant LDL-C lowering. In
addition to LDL-C, other risk factors are likely to influence
residual cardiovascular risk. Among these, lipoprotein(a)
[Lp(a)], has been proposed to be independently associated
with CVD [
8
].
Lp(a) is an low density lipoprotein (LDL) particle
which is attached to the polypeptide, apolipoprotein(a)
[apo(a)] [
9
]. Apo(a) exists in multiple forms or ‘kringles’,
which give rise to different Lp(a) isoforms. Apo(a) is also
believed to be responsible for the anti-fibrinolytic
properties of Lp(a) [
9
]. Further biomechanisms behind the
Lp(a) and CVD relationship may also involve
prothrombotic or proatherosclerotic processes, or a combination
of the two [
10
].
Lp(a) may be measured using a variety of different
assays. However, the reliability of many of the assays is
questionable, due to their poor abilities at detecting the
multiple molecular isoforms of Lp(a). Consequently,
some assays (isoform dependent) that measure Lp(a)
mass cannot distinguish between high and low molecular
weight apo(a) isoforms, whilst others (isoform
independent) can. However, to our knowledge, at present there
appear to be no Lp(a) assays that are both isoform
independent and suited for use clinical laboratories [
11
]. This
problem has led to poor standardisation and comparability
with respect to the Lp(a) values recorded by different
assays, which in turn hampers comparisons between trials
assessing the relationship between Lp(a) and CVD [
12
].
Despite this clinical trials have shown that Lp(a) is a risk
factor in patients on long-term statin treatment [
13, 14
].
Evidence from the Atherothrombosis Intervention in
Metabolic Syndrome with Low HDL/High Triglycerides:
Impact on Global Health Outcomes (AIM-HIGH) trial
suggests that Lp(a) is a predictor of CVD events in
patients with normal LDL-C levels [15] and recent studies
have suggested that elevated Lp(a) levels like elevated
LDL-C, could be associated with premature CVD [
8
].
Extensive research exists to support an association
between Lp(a) and CVD events with respect to the primary
prevention of events in the general population [
16, 17
].
This relationship appears to be independent of LDL-C,
other lipid levels such as high density (...truncated)