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Beyond LDL-cholesterol reduction: the way ahead in managing dyslipidaemia
John Chapman*
National Institute for Health and Medical Research, Hôpital de la Pitié, 83, boulevard de l'hopital, 75651 Paris, Cedex 13, France
* Corresponding author. Tel: +33 1 45 82 81 98; fax: +33 1 45 82 81 98. E-mail address: chapman{at}chups.jussieu.fr
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Abstract
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Observational cohort studies and analysis of the populations
of intervention trials at baseline reveal a strong inverse association
between circulating levels of high-density lipoprotein (HDL)-cholesterol
at baseline and the risk of a fatal or non-fatal cardiovascular
event. Intervention with a statin is as effective, in absolute
terms, in reducing the risk of coronary events in patients across
a wide range of dyslipidaemic phenotypes, including those with
low HDL-cholesterol. However, statins exert little effect on
the levels of HDL-cholesterol, and treatment with a statin does
not eliminate the excess risk associated with low HDL-cholesterol.
Additional therapy is clearly required to address this residual
risk. The success of clinical evaluations of agents that increase
HDL-cholesterol, such as nicotinic acid or fibrate drugs, in
reducing the incidence of cardiovascular events points to a
way forward. Evidence from outcome studies already points to
superior cardiovascular risk reductions in patients receiving
a statin plus nicotinic acid, and intensive multi-drug regimens
based on such combinations probably represent the way to achieve
cardiovascular risk reductions greater than those possible with
a statin alone. Accurate and well-validated assays for measuring
HDL-cholesterol and more precise definition of optimal levels
of HDL-cholesterol in patients with different levels of cardiovascular
risk are required. These advances will facilitate the future
drafting of guidelines that include correction of low HDL-cholesterol
alongside reduction of low-density lipoprotein cholesterol within
clinical algorithms for reducing cardiovascular risk.
Key Words: HDL-cholesterol • Atherosclerosis • Cardiovascular risk • Dyslipidaemia
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Introduction
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HMG-CoA reductase inhibitors (statins) have revolutionized the
management of dyslipidaemia, with up to
30% reductions in the
incidence of cardiovascular events in a broad range of patients,
including patients with diabetes,
1 the elderly,
2 markedly hyperlipidaemic
patients at high cardiovascular risk,
3–5 patients with
acute coronary syndromes,
6,7 and patients without marked elevations
of LDL-cholesterol.
8–10 It is reasonable to attribute
much, though not all, of the outcome benefits observed in these
studies to reductions in the levels of LDL-cholesterol.
11,12 As a result of these landmark trials, current guidelines for
the management of cardiovascular disease place lipid lowering
firmly at the centre of strategies aimed at reducing the risk
of cardiovascular events, with clear performance targets for
LDL-cholesterol for a broad spectrum of non-diabetic dyslipidaemic
patients at low, moderate, or high cardiovascular risk,
13,14 and specifically for patients with type 2 diabetes.
15,16
Lowering LDL-cholesterol is undoubtedly an effective means of controlling cardiovascular risk, but other lipid-modifying strategies are also important in some populations with a poor cardiovascular prognosis. The atherogenic dyslipidaemia associated with insulin- resistant states, such as type 2 diabetes or the metabolic syndrome, is characterized by low high-density lipoprotein (HDL)-cholesterol levels and elevated triglycerides, often accompanied by normal or near-normal levels of LDL-cholesterol.17–19 Accordingly, it is reasonable to suggest that raising HDL-cholesterol is likely to contribute to effective strategies for improving outcomes in many patients with dyslipidaemia. The purpose of this review is to consider the evidence base supporting intervention to correct low HDL-cholesterol levels as a therapeutic target in patients with dyslipidaemia associated with accelerated atherosclerosis.
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HDL-cholesterol and coronary risk
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The Framingham study was the first major observational cohort
study to demonstrate a significant and independent association
between low levels of HDL-cholesterol and an increased risk
of premature mortality.
20 Data gained from 12 years of follow-up
in this study showed that men in the lowest quintile for HDL-cholesterol
[<0.9 mmol/L (<35 mg/dL)] were 3.6 times more
likely to die a cardiovascular death, 4.1 times more likely
to die from a coronary event, and 1.9 times more likely to die
from any cause, compared with those in the highest quintile
[>1.4 mmol/L (>54 mg/dL)].
21 The significant
influence of low HDL-cholesterol on adverse cardiovascular outcomes
in the Framingham study persisted even after multivariate adjustment
for smoking, obesity, alcohol consumption, random blood glucose,
total cholesterol, and blood pressure.
22 Moreover, this and
other studies have demonstrated that low HDL-cholesterol increased
the risk of cardiovascular disease even when LDL-cholesterol
is normal, or near-normal.
22,23 Other epidemiological evaluations
have confirmed these findings. The Atherosclerosis Risk in Communities
study (ARIC) followed 12 339 middle-aged subjects without
coronary heart disease at baseline for 10 years.
24 The risk
of developing coronary heart disease was strongly related to
HDL-cholesterol in women and in men (
Figure 1). A multivariate
analysis based on a proportional hazards model including LDL-cholesterol,
HDL-cholesterol, triglycerides, Lp(a), apolipoprotein (apo)
B, and apoA-I, and adjusted for age, race, smoking, systolic
blood pressure, and requirement for medications for hypertension
or diabetes showed that low HDL-cholesterol was an independent
predictor of coronary heart disease (relative risk 0.76,
P<0.01).
The PROspective CArdiovascular Münster (PROCAM) Study enrolled
20 060 subjects between 1979 and 1985.
25 Of 5389 men who
were between 35 and 65 years of age at enrolment, acute coronary
events occurred in 325. HDL-cholesterol was once again a significant
predictor of coronary disease in a Cox proportional hazards
analysis, and was ranked higher in prognostic importance than
a history of diabetes, a family history of myocardial infarction,
systolic blood pressure, or triglycerides.
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Figure 1 Relationship between HDL-cholesterol at baseline and cardiovascular risk in the Atherosclerosis Risk in Communities Study (ARIC). Adapted with permission from Sharrett, Ballantyne, and Coady et al.24
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Low HDL-cholesterol is commonly found in the general population.
For example, 18% of men and 4% of women in the Framingham Offspring
study had HDL-cholesterol <0.9 mmol/L (<35 mg/dL).
26 Depressed levels of HDL-cholesterol are especially common in
patients with coronary heart disease, as would be expected from
the observational studies described earlier. A survey of 255
men with coronary heart disease in the USA found that 22% had
low HDL-cholesterol without marked elevations of LDL-cholesterol.
27 Moreover, observational studies have shown that HDL-cholesterol
was significantly lower in populations of patients who subsequently
develop coronary heart disease, compared with those who do not.
28 Data from the Health Survey for England show that HDL-cholesterol
<0.9 mmol/L (35 mg/dL) is more common (
P<0.001)
in men with cardiovascular disease (23%) compared with men without
cardiovascular disease (16%).
29 A similar association was found
for women (8 vs. 5%, respectively,
P<0.001). In men or women
aged
35, low HDL-cholesterol was found in 21% of men with ischaemic
heart disease or stroke, compared with 17% of men without these
conditions (
P<0.001), with corresponding figures for women
>35 years of 10 and 5%, respectively (
P<0.001).
These and other data confirm the potential of correcting low HDL-cholesterol for the management of cardiovascular risk. The following sections of this review will focus on therapeutic strategies designed for intervention in this population.
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Do statins eliminate the elevated coronary artery disease risk associated with low HDL-cholesterol at baseline in intervention trials?
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Data from some of the major intervention trials with statins
have been stratified for HDL-cholesterol at baseline.
30 These
include the West of Scotland Coronary Prevention Study (WOSCOPS),
2 pooled data from the Cholesterol and Recurrent Events (CARE)
8 and the Long-term Intervention with Pravastatin in Ischemic
Disease (LIPID)
31 trials, the Scandinavian Simvastatin Survival
Study (4S),
4 and the Air Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/TexCAPS).
9 The incidence of cardiovascular
events in all of these trials was inversely proportional to
the level of HDL-cholesterol at baseline (
Figure 2). These findings
are consistent with the status of low HDL-cholesterol as an
independent risk factor for cardiovascular disease, as defined
in epidemiological studies and described earlier.
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Figure 2 Incidence of coronary events in patients randomized to a statin or to placebo stratified for HDL-cholesterol at baseline in major intervention trials. Adapted from Sacks with permission from Excerpta Medica Inc.30
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Treatment with a statin provided similar absolute reduction
in cardiovascular risk at all levels of HDL-cholesterol, as
the curves for active treatment and placebo in
Figure 2 were,
in general, roughly parallel. Thus, a similar relationship between
the levels of HDL-cholesterol and cardiovascular risk holds
in patients treated with a statin or placebo. While statins
are clearly of benefit in patients with low HDL-cholesterol,
they do not eliminate the excess risk associated with low HDL-cholesterol,
and additional treatment to rectify this problem may be required.
30
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Are innovative treatment strategies available to raise HDL-cholesterol levels efficaciously in patients with dyslipidaemia characterized by low HDL-cholesterol?
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Statins mainly influence levels of LDL-cholesterol or other
apoB-containing lipoproteins.
11,12,32 The effects of these drugs
on the levels of HDL-cholesterol are relatively minor, with
increases of
3–12% obtained with their usual doses, and
it is unclear at present whether the effects of statins on HDL-cholesterol
are clinically relevant.
33 Adding HDL-cholesterol-raising therapies
to a statin increases the effects on HDL-cholesterol, with treatment
based on the combination of a statin and nicotinic acid providing
the largest increases in HDL-cholesterol (
Table 1).
34–49 Increases in HDL-cholesterol of
30–40% were observed in
angiographic outcome trials such as the HDL Atherosclerosis
Treatment Study (HATS),
38 the Familial Atherosclerosis Treatment
Study (FATS),
39,40 and the Cholesterol Lowering Atherosclerosis
Study (CLAS-I),
35 all with combination regimens based on adding
nicotinic acid to a statin (
Table 1). Importantly, the effectiveness
in reducing the risk of cardiovascular events of these combination
treatments, which increase HDL-cholesterol and reduce LDL-cholesterol
simultaneously, was markedly greater than the effectiveness
in other studies of treatment based on a statin alone, which
mainly reduces LDL-cholesterol (
Figure 3).
3,4,10,38,39,40,50,51 In the past, the use of nicotinic acid for lipid modification
has been limited to an extent by side-effects, particularly
flushing. Previous attempts to overcome this problem with the
use of slow-release preparations combated the flushing with
great success, but unfortunately led to the appearance of liver
side-effects. A new prolonged-release formulation of nicotinic
acid (Niaspan
®) appears to address both issues, with fewer
flushing episodes than immediate-release preparations, and with
a very low potential for side-effects in the liver.
14,52,53 Long-term evaluations demonstrate that the efficacy of this
treatment combined with a statin is durable over time, with
marked elevations in HDL-cholesterol and substantial reductions
in LDL-cholesterol, triglycerides, and in the atherogenic lipoprotein,
Lp(a) (
Figure 4).
54,55 It is of particular interest to note
that the HDL-raising action of Niaspan
® combined with a
statin in this study led to progressive HDL elevation over the
entire study period, with an increase of 41% achieved after
52 weeks of treatment.
55
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Figure 3 Comparison of relative risk reductions (RRR) from intervention studies that evaluated statin monotherapy (open columns), or combination regimens including nicotinic acid and a statin (filled columns). ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial (lipid-lowering arm);10 CARDS, Collaborative Atorvastatin Diabetes Study;50 HPS: Heart Protection Study;3 LDL-C, low density lipoprotein cholesterol; PPP, Pravastatin Pooling Project;51 (which pooled data from WOSCOPS).5
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Looking ahead: future management of low HDL-cholesterol
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HDL-cholesterol and management guidelines
Low HDL-cholesterol is generally accepted as a level <1 mmol/L
(<40 mg/dL) in men and <1.2 mmol/L (<50 mg/dL)
in women. At present, however, the importance of controlling
HDL-cholesterol is not adequately reflected in international
guidelines for the management of dyslipidaemia. Although a wealth
of evidence identifies low HDL-cholesterol as an important and
independent risk factor for adverse cardiovascular outcomes
(aforementioned), these guidelines tend to regard low HDL-cholesterol
more as a marker of risk, and as a component of the data package
required for global cardiovascular risk calculators. For example,
those current in Europe, complied by eight societies (European
Association for the Study of Diabetes, International Diabetes
Federation Europe, European Atherosclerosis Society, European
Heart Network, European Society of Cardiology, European Society
of Hypertension, European Society of Behavioral Medicine, European
Society of General practice/Family Medicine), consider that
‘No specific treatment goals are defined for HDL-cholesterol
and triglycerides, but concentrations of HDL-cholesterol and
triglycerides are used as markers of increased risk’.
13 Guidelines from the USA state that ‘A specific HDL-cholesterol
goal level to reach with HDL-raising therapy is not identified.
However, non-drug and drug therapies that raise HDL-cholesterol
levels and are part of management of other lipid and non-lipid
risk factors should be encouraged. There is not enough evidence
to make recommendations for incorporating HDL-cholesterol (HDL-C)
levels in the recommendations on therapy, although HDL-C measurement
is still required because it forms part of coronary risk assessment
within the coronary risk charts’.
14 National guidelines
tend to follow. The highly regarded UK National Institute for
Clinical Excellence has produced guidelines for the management
of lipids in patients with type 2 diabetes.
56 Low HDL-cholesterol
is a particularly acute problem in this population, yet the
guidelines state that ‘There is not enough evidence to
make recommendations for incorporating HDL-cholesterol (HDL-C)
levels in the recommendations on therapy, although HDL-C measurement
is still required because it forms part of coronary risk assessment
within the coronary risk charts’.
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Discussion
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Substantial, and growing, epidemiological evidence has associated
low HDL-cholesterol with an increased risk of morbid cardiovascular
events. Treatment with a statin provides clinically significant
benefits in terms of improved clinical outcomes in patients
with low HDL-cholesterol, as in other populations. However,
subgroup analyses of major intervention trials with statins
show clearly that statin treatment leaves the additional cardiovascular
risk associated with low HDL-cholesterol relatively untouched.
It is reasonable to believe that intervening to increase levels
of HDL-cholesterol may provide a means of improving outcomes
in these patients. A group of physicians working in the field
of dyslipidaemia (
Table 2) recently came together under the
banner of the European Consensus Panel on HDL-C to discuss the
growing evidence supporting HDL-cholesterol as an important
risk factor for cardiovascular disease, and to suggest ways
forward to improve patient care in this area. The group produced
a position paper containing a series of recommendations.
57
First, several methods of measuring HDL-cholesterol are in use,
and this requires rationalization. An accurate and reproducible
clinical laboratory assay for HDL-cholesterol is required, with
broad international standardization. This will facilitate the
design of more detailed guidelines that recognize the heterogeneity
of low HDL-cholesterol dyslipidaemias, with ‘low’
and ‘optimal’ levels of HDL-cholesterol identified
for men and women with different levels of global coronary heart
disease risk. Defining optimal levels of HDL-cholesterol is
seen as particularly urgent in the setting of the metabolic
syndrome or type 2 diabetes, where isolated low HDL-cholesterol
is commonly found as part of a highly atherogenic lipid profile.
A working group in the USA reached similar conclusions regarding
the importance of low HDL-cholesterol as a therapeutic target,
and recommended ‘more frequent and more aggressive’
intervention to correct low HDL-cholesterol.
58
The improvements in the measurement and definitions of low HDL-cholesterol implicit in these recommendations will support the future recognition of low HDL-cholesterol alongside raised LDL-cholesterol as a valid therapeutic target for intervention. Indeed, correction of low HDL-cholesterol should appear in management algorithms in its own right. Given the likely need for intensive interventions based on lifestyle interventions and combinations of several lipid-modifying drugs, the Panel also noted the potential of nicotinic acid combined with primary statin therapy as a useful treatment option for normalizing lipid profiles and improving patient outcomes.
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Conclusions
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Low HDL-cholesterol is an independent risk factor for cardiovascular
disease. Future updates of management guidelines for dyslipidaemia
should reflect this more strongly, with intervention to correct
low HDL-cholesterol included alongside intervention to lower
elevated LDL-cholesterol as rational strategies for reducing
cardiovascular risk. Adding HDL-cholesterol raising therapy,
such as prolonged-release nicotinic acid, to a statin appears
a promising and rational means of improving patient outcomes
beyond that possible with either therapy alone.
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Abstract
Introduction
9.0 mmol/L (