Download The realities of dyslipidaemia: what do the studies tell us?

European Heart Journal Supplements (2005) 7 (Supplement F), F27–F33
doi:10.1093/eurheartj/sui040
The realities of dyslipidaemia: what do the studies
tell us?
John J.P. Kastelein*
Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
KEYWORDS
HDL-cholesterol;
Atherosclerosis;
Cardiovascular risk;
Dyslipidaemia;
Evidence-based medicine
Well-designed studies have established the benefits of statins in populations with
widely differing overall cardiovascular risk. Statins reduce LDL-cholesterol in all of
these populations, in some cases to a level well below guideline targets. The
effects of statins on cardiovascular outcomes are remarkably similar between
studies, with the incidence of cardiovascular events reduced relative to placebo
by not more than 40% in any study and usually by 10–30%. Addressing other
cardiovascular risk factors will be necessary to generate additional benefits. Atherosclerosis is increasingly considered an inflammatory disease, and reducing markers of
inflammation, such as C-reactive protein, may prove beneficial. However, intervention with agents that increase HDL-cholesterol is already supported by substantial
clinical evidence. A number of well-designed evaluations of fibrates and nicotinic
acid, which act mainly by raising levels of HDL-cholesterol, have demonstrated significant improvements in outcomes in populations at high risk of cardiovascular
events. Combinations of nicotinic acid with a statin have been shown to halt or
reverse the progression of atherosclerosis, in the HDL Atherosclerosis Treatment
Study (HATS) and in the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial. Nicotinic acid–statin combination therapy has produced
the largest improvements in clinical outcomes so far achieved, with a reduction in
cardiovascular events of 60–90% relative to placebo in HATS. Nicotinic acidbased combinations are a rational and an evidence-based approach to improve
cardiovascular outcomes to a greater extent than is currently possible with statins
alone.
Introduction
We live in the era of evidence-based medicine, and
our routine clinical practice must be firmly based on
the lessons learnt from well-designed clinical trials.
Fortunately, the preceding decade has seen an explosive
increase in the breadth and depth of clinical information
since the publication of the Scandinavian Simvastatin
Survival Study (4S)1 in 1994 and the West of Scotland
Coronary Prevention Study Group (WOSCOPS)2 with
* Corresponding author. Tel: þ31 20 566 6612; fax: þ31 20 566 9343.
E-mail address: [email protected]
pravastatin in 1995. Indeed, a series of landmark studies
have defined the potential of statin-based therapy using
a variety of agents of this type in a range of distinct
patient populations. We now know a great deal concerning the efficacy of statins on lipid profiles and clinical
endpoints and also their limitations in reducing the risk
of coronary disease.
This is an opportune time to stand back for a moment
and consider the results of these trials and their implications for the future of clinical research and cardiovascular care. This review sets out to evaluate the
therapeutics of statins in comparison with other lipidmodifying interventions, in patients at elevated risk of
premature coronary death.
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]
F28
J.J.P. Kastelein
Lifestyle interventions and outcomes
in dyslipidaemia
Lifestyle-based interventions, such as dietary modifications, have been shown to exert beneficial effects on
the lipid profile in some studies. For example, the Boeing
Employees Fat Intervention Trial (beFIT)3,4 evaluated the
effects of the ‘Step II’ diet, recommended by the National
Cholesterol Education Program (NCEP). This diet sets an
upper limit for a total fat of ,30% of caloric intake, and
for saturated fat of 7% of total caloric intake, with the
stated intention of reducing levels of LDL-cholesterol.5
The beFIT study had the advantages of being of adequate
size (n ¼ 383), together with a randomized design and an
intent-to-treat analysis. Patients were taught the NCEP
diet in eight weekly classes, followed by continued
support through quarterly counselling sessions. The mildly
dyslipidaemic patients in beFIT were stratified on the basis
of gender and their lipid profiles at baseline, defined as
hypercholesterolaemic (elevated LDL-cholesterol) or
combined hyperlipidaemic (elevated LDL-cholesterol and
triglycerides) to produce four groups. LDL-cholesterol
decreased by 8–9% (P , 0.01) in men or women with
hypercholesterolaemia or combined hyperlipidaemia after
6 months of follow-up. HDL-cholesterol was also decreased
at this time point to a greater extent in women (by 5–6%
from baseline, P , 0.01) than in men (by 1–3% of baseline,
P ¼ NS). After 1 year, these decreases in HDL-cholesterol
were maintained in hypercholesterolaemic women
(27.6%, P , 0.01) and men (21.3%, P ¼ NS), whereas
modest decreases of 3–5% from baseline occurred in men
and women with combined hyperlipidaemia.
The beFIT trial was not an outcomes study. However,
the Lyon Diet Heart Study provides an illustration of the
benefits that may be available from dietary modification.
Patients assigned to a Mediterranean-style diet, low in
saturated fat and cholesterol for 5 years, benefited
from a significant reduction in the risk of a range of
cardiovascular endpoints, including myocardial infarction
(Figure 1 ).6 Unfortunately, it is difficult to attribute
these benefits to lipid modification, as classic lipid parameters differed little between the intervention and the
control groups in this study.
Intake of viscous fibre, e.g. guar gum, pectin, oat gum,
or psyllium, in quantities of 2–10 g/day has also been
shown to reduce LDL-cholesterol by 6–7%.7 Similarly,
intake of plant stanols or sterols (1–3 g/day) may provide
a reduction in LDL-cholesterol of 5%.7 Drinks,8
yoghurts,8,9 and spreads10 enriched in stanols or sterols
are available and provide a convenient and effective
means of delivering these dietary treatments. Overall,
these interventions may be considered to be equivalent
to losing 4–5 kg (10 lb) of body weight.7 In addition,
other lifestyle-based interventions, such as smoking cessation and exercise, will also exert beneficial effects on HDLcholesterol, in particular.5 As such, these interventions
provide a useful starting point for the design of lipid-modifying therapy and are thus strongly supported by guidelines
as a first step in correcting dyslipidaemia.5,11 However,
in many cases, the limited magnitude of these effects
may require the addition of pharmacological therapy to
Figure 1 Reduced incidence of non-fatal myocardial infarction in
patients maintained on a Mediterranean diet in the Lyon Diet Heart
Study.6 aDietary intervention with canola (rapeseed) oil-based margarine,
fibre, low cholesterol, low saturated fat, fruits, and vegetables.
Reproduced with permission from: de Lorgeril M et al. 6
the regimen, particularly as improvements in risk factors
through lifestyle intervention are notoriously difficult to
maintain over the long-term.12
Evidence from major statin trials
Efficacy in overall patient populations
A paucity of effective medications and limitations in the
design of clinical trials and collection of endpoints
limited the success of early evaluations of lipid-modifying
therapy in the pre-statin era. An early review of available
trials, published in 1992, concluded that ‘lowering serum
cholesterol concentrations does not reduce mortality
and is unlikely to prevent coronary artery disease’.13
Fortunately, some of the landmark trials that would
later refute this hypothesis were already under way.14,15
Today, the results of large, well-designed evaluations of
various statins are available to guide evidence-based
therapy for patients with varying degrees of cardiovascular risk. For example, the Air Force/Texas Coronary
Atherosclerosis Prevention Study (AFCAPS/TexCAPS)16
recruited a relatively low-risk patient population without
a prior history of cardiovascular events, with average
total cholesterol and LDL-cholesterol (the purpose of this
study was to evaluate the effects of the statin in patients
with isolated low HDL-cholesterol). At the other end of
the scale, the 4S study was a secondary prevention study
in a high-risk population of patients with established
coronary heart disease and hypercholesterolaemia.1 A
number of other trials have evaluated statins in patients
with intermediate levels of overall cardiovascular
risk.2,17–22 (Figure 2 ).
The primary endpoints of these trials were typically
composites of coronary death and vascular events,
although total mortality was the primary endpoint in
4S. The effects of the statins on clinical outcomes
(Figure 3 ) were remarkably similar, given the differences
Realities of dyslipidaemia
Figure 2 Spectrum of cardiovascular risk in patient populations from
selected randomized evaluations of statins. aOr other cardiovascular
risk factor and bCHD or CHD risk equivalent, e.g. diabetes. CHD, coronary
heart disease. Scandinavian Simvastatin Survival Study (4S),1 Long-Term
Intervention with Pravastatin in Ischaemic Disease (LIPID) Study,18 PROspective Study of Pravastatin in the Elderly at Risk (PROSPER),19 Heart
Protection Study (HPS),19 Cholesterol and Recurrent Events (CARE)
study,17 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT-LLT),21 Anglo-Scandinavian Cardiac Outcomes
Trial–Lipid Lowering Arm (ASCOT-LLA),22 West of Scotland Coronary
Prevention Study Group (WOSCOPS),2 Air Force/Texas Coronary
Atherosclerosis Prevention Study (AFCAPS/TexCAPS).16
Figure 3 Effectiveness of statins on the risk of the primary endpoint in
randomized, controlled trials. See Figure 2 for full names and references
for quoted clinical trials.
in the absolute cardiovascular risk of these patient populations, on average. Overall, intervention with a statin
reduced the incidence of cardiovascular events by
25–30% across all of the studies. A meta-analysis of
five trials, based on a total of 30 817 patients, found
that an average reduction in LDL-cholesterol of 28% was
associated with a 31% reduction in major coronary
events, consistent with these findings.23 Therefore, it
appears that as many as 70% of the cardiovascular
events were not prevented by statins in these clinical
trials.
Efficacy of statins according to age
and lipids at baseline
Age
The Heart Protection Study (HPS) included a substantial
proportion of subjects aged 70 (n ¼ 5806, 28% of the
total study population).20 Intervention with simvastatin
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in these individuals produced a reduction in the risk of
a first major vascular event of 18%, relative to placebo,
which did not differ significantly from the 23% relative
risk reduction observed in 9839 patients aged ,65
years. The PROSPER study set out to recruit an elderly
population, with a recruitment criterion of age 70–82
at screening and an average age of 75 years at baseline.19
These patients were also at high cardiovascular risk due
to a history of coronary heart disease or risk factors signifying an increased global cardiovascular risk, although
LDL-cholesterol was only mildly elevated at baseline
[mean value 3.8 mmol/L (147 mg/dL)]. The protection
afforded by the statin was within the range of that
observed in other statin trials (Figure 3 ), with a 15%
reduction in the risk of the combined primary endpoint
coronary heart disease death, non-fatal myocardial
infarction, or any stroke, and a 19% reduction in the
risk of death from coronary heart disease or non-fatal
myocardial infarction. Clearly, statins are as effective
in the elderly as in other populations.
Extent of lipid lowering
Subgroup analyses in the HPS also included stratification
based on patients’ LDL-cholesterol at baseline. The
effects of simvastatin on LDL-cholesterol were essentially
identical across these subgroups, with average placebocorrected reductions of 0.9 mmol/L (35 mg/dL) for
patients with LDL-cholesterol ,3.0 mmol/L (,116 mg/dL),
and 1.0 mmol/L (40 mg/dL) in the groups with LDLcholesterol 3.0 mmol/L and ,3.5 mmol/L (,135 mg/dL)
or 3.5 mmol/L. Mean final LDL-cholesterol was 1.8,
2.2, and 2.7 mmol/L, respectively, for the three subgroups. Little difference in the reduction in the risk of
a first major cardiovascular event was apparent among
these groups, despite different lipid levels achieved or
in a fourth subgroup with LDL-cholesterol ,2.6 mmol/L
(,100 mg/dL) at baseline (Figure 4 ).
The Collaborative Atorvastatin Diabetes Study (CARDS)
also evaluated the potential of achieving low levels of
LDL-cholesterol on the incidence of cardiovascular
events.24 Patients eligible for CARDS did not have
markedly elevated LDL-cholesterol [4.14 mmol/L
(160 mg/dL) at baseline] or a history of cardiovascular
disease. However, the presence of type 2 diabetes and at
least one risk factor for adverse cardiovascular outcomes
(retinopathy, albuminuria, smoking, or hypertension) signified a high global cardiovascular risk. The study was terminated after an average of 3.9 years of follow-up, 2 years
earlier than planned as efficacy endpoints had been met. In
patients randomized to atorvastatin, mean LDL-cholesterol declined from 3.0 mmol/L (117 mg/dL) at baseline
to 2.1 mmol/L (82 mg/dL) at study end, a reduction from
baseline of 40% (P , 0.0001), whereas HDL-cholesterol
was essentially unchanged. This profound reduction in
LDL-cholesterol was accompanied by a reduction in the
risk of major cardiovascular events of 37% (P ¼ 0.001).
Thus, CARDS demonstrated a reduction in cardiovascular
endpoints comparable to that shown for hypercholesterolaemic patients in Figure 3 in a patient population
who achieved, on average, LDL-cholesterol levels well
below the target value of 2.6 mmol/L (100 mg/dL)
F30
Figure 4 Incidence of major vascular events according to patients’
levels of LDL-cholesterol at baseline in the HPS.20 Numbers above
columns are relative risk reductions.
recommended by current guidelines for the management
of dyslipidaemia in diabetic patients.25
A further trial set out to test the hypothesis that the profound lowering of LDL-cholesterol with a statin should
provide additional clinical benefits over usual care strategies with these agents. The Pravastatin or Atorvastatin
Evaluation and Infection Therapy (PROVE-IT) trial compared the effects of intensive lipid-lowering therapy
with atorvastatin 80 mg [target level 1.7 mmol/L
(65 mg/dL)] with those of ‘standard’ lipid-lowering
therapy with pravastatin 40 mg [target level 2.5 mmol/L
(95 mg/dL)] in patients hospitalized for acute coronary syndromes (myocardial infarction or unstable
angina).26,27 The LDL-cholesterol targets were achieved,
with mean values of 1.6 mmol/L (62 mg/dL) in the intensive group and 2.5 mmol/L (95 mg/dL) in the ‘usual care’
group at study end. The incidence of a combined endpoint
comprising all-cause mortality or major cardiovascular
events was significantly lower in the intensive therapy
group (16% risk reduction vs. the ‘usual care’ group,
P ¼ 0.005).
Beyond LDL-cholesterol lowering
C-reactive protein
The PROVE-IT investigators attributed the additional
reduction in event rates on the atorvastatin regimen to
the additional LDL-cholesterol lowering observed in this
arm.27 However, the study design was complicated by
the use of different statins, which may have different
effects on parameters other than LDL-cholesterol. The
reversal of atherosclerosis with aggressive lipid lowering
(REVERSAL) trial also compared pravastatin 40 mg with
atorvastatin 80 mg, with angiographic measurements of
atheroma volume as the primary endpoint, in a total of
657 patients requiring angioplasty for coronary artery
disease.28 Mean LDL-cholesterol declined significantly
(P , 0.001) from 3.9 mmol/L (150 mg/dL) at baseline
J.J.P. Kastelein
Figure 5 Effects of intensive and moderate lipid lowering strategies on
the progression of atherosclerosis and plasma C-reactive protein in the
Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL)
trial.28 P , 0.001 vs. baseline (angiographic data only). Indices of
atheroma progression are median values.
in either treatment group to 2.8 mmol/L (110 mg/dL) in
the pravastatin group and to 2.0 mmol/L (79 mg/dL) in
the atorvastatin group. Atheroma burden progressed
significantly in the pravastatin (moderate lipid-lowering)
group, but did not change significantly in the atorvastatin
(intensive lipid-lowering) group relative to baseline, with
a significant difference between these treatments
(Figure 5A and B ).
The greater reduction in atheroma burden in the intensive lipid-lowering group in the REVERSAL trial is consistent with the further improvement in clinical outcomes,
beyond that provided by moderate lipid lowering, with
the intensive regimen in PROVE-IT. It is tempting to
attribute this additional benefit to the lower levels of
LDL-cholesterol achieved with the intensive regimen.
However, other mechanisms may be involved. The REVERSAL investigators measured levels of plasma C-reactive
protein, in addition to lipoproteins. To their surprise,
atorvastatin was markedly and significantly more effective in reducing C-reactive protein than pravastatin
(Figure 5C ). Inflammatory processes are increasingly
being implicated in the pathogenesis of atherosclerosis,29
and C-reactive protein is an acute phase protein that provides a marker of the presence of inflammation of any
aetiology.30 Elevated C-reactive protein is a useful
marker of increased cardiovascular risk, despite its lack
of specificity as to the source of the inflammation and
correlates with indices of atherogenic and thrombotic
risk.31,32 Indeed, following 8 years of follow-up of
27 939 healthy women in the USA, the highest quintile
of C-reactive protein was associated with a greater
risk of a first cardiovascular event than the highest
quintile of LDL-cholesterol (relative risks 2.3 vs. 1.5,
respectively).33
HDL-cholesterol raising
Correcting low HDL-cholesterol provides an alternative
means of reducing cardiovascular risk,34–36 whether
or not LDL-cholesterol is elevated.37 Interestingly, the
Realities of dyslipidaemia
phenomena of inflammation, low HDL-cholesterol, and
increased cardiovascular risk may be connected. A
9-year study of 245 participants of the Physicians
Health Study who went on to develop myocardial infarction (cases) and 372 subjects who remained free of cardiovascular disease (controls) focused on the prognostic
importance of C-reactive protein and HDL-cholesterol.38
Cases had significantly (P ¼ 0.008) lower HDL-cholesterol
[1.2 mmol/L (46 mg/dL)] than controls [1.3 mmol/L
(49 mg/dL)] and significantly higher total-cholesterol:
HDL-cholesterol ratios (5.3 vs. 4.5, P ¼ 0.001), as would
be expected. Apparently healthy men in the highest
tertile of total-cholesterol: HDL-cholesterol ratio (.5.01)
and C-reactive protein (.1.69 mg/L) were at a 4.4-fold
higher risk of a first myocardial infarction when compared
with patients in the lowest tertiles for these parameters
(,3.78 and ,0.72 mg/L, respectively). For comparison,
the relative risks of a first myocardial infarction were 2.8
for high total cholesterol:LDL-cholesterol ratio (and low
C-reactive protein) and 1.3 for high C-reactive protein
(and low total cholesterol:LDL-cholesterol ratio).
Interventions to correct low HDL-cholesterol have
demonstrated statistically and clinically significant
reductions in the incidence of cardiovascular events. The
Veterans Affairs HDL intervention trial (VA-HIT) demonstrated a reduction of 24% vs. placebo (P ¼ 0.006) in the
risk of a coronary event during 5.1 years of treatment
with a fibrate (gemfibrozil) in a patient population with
prior myocardial infarction and low HDL-cholesterol
[1.0 mmol/L (40 mg/dL)] at baseline.39 Data from
the VA-HIT population stratified for HDL-cholesterol
after treatment show a clear association between low
HDL-cholesterol and increased cardiovascular risk
(Figure 6 ).39–41 A multivariate analysis (Cox proportional
hazards model corrected for age, smoking, diabetes,
hypertension, and body mass index) explored the relationships between levels of individual lipid components and
the risk of a combined endpoint of death from coronary
heart disease or non-fatal myocardial infarction in
VA-HIT.40 This analysis revealed a significant association for HDL-cholesterol [relative risk 0.89 (95% CI
Figure 6 Relationship between HDL-cholesterol and cardiovascular outcomes in the VA-HIT.39–42 Reprinted from Sacks FM. & 2002 with permission from Excerpta Medica Inc.41
F31
0.81–0.98), P ¼ 0.02], but no significant association for
LDL-cholesterol [relative risk 1.09 (95% CI 0.98 to 1.21),
P ¼ 0.13] or triglycerides [relative risk 1.03 (95% CI
0.95–1.11), P ¼ 0.48]. These data confirm the earlier
finding from the Helsinki Heart Study in a population
without low HDL-cholesterol at baseline that fibratebased therapy produces outcome benefits that are
largely due to increases in HDL-cholesterol.42
Further studies have evaluated the effects on cardiovascular outcomes of nicotinic acid, which is the most
effective agent currently available for raising HDLcholesterol.43 The Coronary Drug Project demonstrated
significant improvements in cardiovascular endpoints,
including a 14% decrease in the incidence of coronary
death plus non-fatal myocardial infarction (P , 0.05), in
a population of almost 4000 patients with a history of
coronary heart disease randomized to nicotinic acid or
placebo.44 A significant benefit for nicotinic acid in
terms of reduced overall mortality (relative risk reduction
211%, P ¼ 0.0004) and coronary heart disease death (relative risk reduction 212%, P , 0.01) persisted for 9 years
after the end of the study, i.e. 15 years after the initial
randomization.45
The largest improvements in cardiovascular outcomes
have been observed in patients receiving combinations
of a nicotinic acid plus a statin. The HATS46 randomized
patients with low HDL-cholesterol [men: 0.9 mmol/L
(35 mg/dL); women: 1.0 mmol/L (40 mg/dL)] to
double-blind treatment with nicotinic acid plus simvastatin, or placebo, with or without additional antioxidant
vitamins. After 3 years of treatment, average changes
from baseline in HDL-cholesterol of 29% and LDLcholesterol of 243% in the nicotinic acid group were
associated with angiographic evidence of regression of
coronary atherosclerosis and a 60–90% reduction in the
incidence of major coronary events (P 0.03).
Discussion
The trials evaluating statin monotherapy have demonstrated highly reproducible and similar outcome benefits
in widely varying patient populations. These agents are
quite rightly now regarded as the mainstay of pharmacological treatment for correcting hyperlipidaemia.
However, the maximum benefit of this approach in
recent trials evaluating intensive LDL-cholesterol lowering seems to have reached a plateau at an approximate
20–40% reduction in the incidence of coronary events.
Three more randomized outcome studies evaluating the
effects on lipids and outcomes with intensive control of
LDL-cholesterol (high-dose statins), in comparison with
less intensive regimens (low-dose statins), are in progress
and will report in the near future. These are the Study
Evaluating Additional Reduction in Cholesterol and
Homocysteine (SEARCH) trial, comparing simvastatin
20 mg with simvastatin 80 mg,47 the Treating to New
Targets (TNT) trial,48 evaluating atorvastatin 10 mg and
atorvastatin 80 mg, and the Incremental Decrease in
End Points through Aggressive Lipid Lowering (IDEAL)
F32
study49 which is evaluating atorvastatin 80 mg in comparison with simvastatin 20 mg. The intensive therapy
aims of these trials are expected to achieve mean LDLcholesterol concentrations substantially ,2.6 mmol/L
(100 mg/dL) and will verify, for example, whether a
50% reduction in this parameter can achieve a 50%
reduction in cardiovascular events. Given the evidence
currently available, however, it seems likely that lowering LDL-cholesterol alone may not be enough to markedly
improve cardiovascular outcomes beyond these levels,
and intervention on other factors little affected by
these agents is required to break through to higher
outcome benefits.
Low HDL-cholesterol is common among patients with
dyslipidaemia, and a wealth of evidence from epidemiological studies and clinical trials shows that increasing
HDL-cholesterol markedly reduces the risk of adverse
cardiovascular outcomes. Nicotinic acid is the most
effective agent for increasing levels of HDL-cholesterol
currently available for clinical use.50 The improvements
in clinical outcomes observed in the HATS trial, obtained
using a statin plus nicotinic acid, were clearly larger than
those seen with statins alone in previous trials. Although
these large improvements require confirmation in other
studies, they are supported by the results of an openlabel follow-up of 176 patients previously enrolled in a
double-blind, randomized evaluation of the effects of
nicotinic acid þ a statin þ a bile acid sequestrant on the
progression of coronary atherosclerosis.51,52 Among 75
patients who remained on the triple regimen, 1.3% died
during 10 years of follow-up when compared with 19.8%
of 101 patients returning to usual care under their own
physician (P , 0.001). Similarly, the incidence of cardiovascular events was reduced in the triple therapy groups,
relative to usual care group (5.3 vs. 18.8%, P , 0.05).
Moreover, nicotinic acid-based regimens have been
shown to slow the progression of atherosclerosis. The
double-blind, randomized, Arterial Biology for the
Investigation of the Treatment Effects of Reducing
Cholesterol (ARBITER) 2 trial compared the effects of
12 months’ treatment with a prolonged release
preparation of nicotinic acid (Niaspanw) at a dose of
1000 mg once-daily with those of placebo in 167 statintreated patients with a history of coronary disease,
low HDL-cholesterol [,1.2 mmol/L (,45 mg/dL)], and
reasonably well-controlled LDL-cholesterol [,3.4 mmol/L
(,130 mg/dL)].53 There was no significant progression
of atherosclerosis in the Niaspanw group, whereas atherosclerosis progressed significantly on placebo. Actual
regression of atherosclerosis with a statin plus nicotinic
acid was observed in subgroups of patients with the
most severe coronary atherosclerosis at baseline in the
HATS trial. Regression of atherosclerosis has not been
observed with statin monotherapy; even the intensive
statin regimen in the REVERSAL trial no more than
halted its progression. Taken together, the current
trial data suggest that the additive benefits available
from simultaneous HDL-cholesterol raising and LDLcholesterol lowering hold the key to achieving the next
breakthrough in improving clinical outcomes in patients
with dyslipidaemia.
J.J.P. Kastelein
Conclusions
Treatment with statins produces similar reductions in
cardiovascular risk irrespective of patients’ age, lipid
profile at baseline, or level overall cardiovascular risk.
Even intensive lowering of LDL-cholesterol with these
agents to levels well below current guideline targets
has not reduced the risk of cardiovascular events by
.20–40%, although trials in progress will ascertain
whether 50% reductions in LDL-cholesterol translate to
a similar proportional reduction in the frequency of cardiovascular events. Addressing other cardiovascular risk
factors in addition to LDL-cholesterol, particularly the
common problem of low HDL-cholesterol, may hold the
key to achieve further improvements in outcomes
beyond those delivered by intensive statin monotherapy.
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