Fruchart et al. Cardiovascular Diabetology 2014, 13:26
http://www.cardiab.com/content/13/1/26
REVIEW
CARDIO
VASCULAR
DIABETOLOGY
Open Access
Residual macrovascular risk in 2013: what have
we learned?
Jean-Charles Fruchart1,2*, Jean Davignon3, Michel P Hermans4, Khalid Al-Rubeaan5, Pierre Amarenco6,
Gerd Assmann7, Philip Barter8, John Betteridge9, Eric Bruckert10, Ada Cuevas11, Michel Farnier12, Ele Ferrannini13,
Paola Fioretto14, Jacques Genest15, Henry N Ginsberg16, Antonio M Gotto Jr17, Dayi Hu18, Takashi Kadowaki19,
Tatsuhiko Kodama20, Michel Krempf21, Yuji Matsuzawa22, Jesús Millán Núñez-Cortés23, Carlos Calvo Monfil24,
Hisao Ogawa25, Jorge Plutzky26, Daniel J Rader27, Shaukat Sadikot28, Raul D Santos29, Evgeny Shlyakhto30,
Piyamitr Sritara31, Rody Sy32, Alan Tall33, Chee Eng Tan34, Lale Tokgözoğlu35, Peter P Toth36, Paul Valensi37,
Christoph Wanner38, Alberto Zambon14, Junren Zhu39, Paul Zimmet40 and for the Residual Risk Reduction
Initiative (R3i)
Abstract
Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity,
metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate
the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction
Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic
triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins
(as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk,
especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of
atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic
dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and
adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic
dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment
decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin
(North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further
reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging
treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists,
cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase
subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i
believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic
dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.
Keywords: Residual cardiovascular risk, Atherogenic dyslipidaemia, Type 2 diabetes, Therapeutic options
* Correspondence: jean-charles.fruchart@r3i.org
1
R3i Foundation, St. Alban-Anlage 46, Basel, CH 4010, Switzerland
2
Fondation Cœur et Artères, Lille, France
Full list of author information is available at the end of the article
© 2014 Fruchart et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication
waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise
stated.
Fruchart et al. Cardiovascular Diabetology 2014, 13:26
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Introduction
Cardiovascular disease (CVD) remains the leading cause
of death and a major cause of disability affecting quality
of life [1,2]. Despite best evidence-based strategies,
including high-dose statin therapy, it is clear that there
persists an unacceptably high residual risk of CV events.
According to the Residual Risk Reduction Initiative
(R3i), residual CV risk is defined as the risk of CV events
that persists in people despite achievement of treatment
goals for low-density lipoprotein (LDL) cholesterol, blood
pressure, and glycaemia according to current standards
of care.
This clinical challenge is exacerbated by the pandemics of obesity, metabolic syndrome and type 2
diabetes. Diabetes prevalence is increasing in almost
every country; globally, it is estimated that diabetes affects
over 371 million people and costs US$471 billion [3].
However, the burden of diabetes is likely to be even greater
in emerging economies in Asia, Africa and the Middle East.
The reasons for this are multifactorial and include transition to an increasingly urbanised, sedentary society
resulting in increasing obesity across the socioeconomic spectrum, as well as early life influences, such as maternal nutrition and newborn overfeeding, which are
associated with epigenetic changes that increase the
risk of obesity, diabetes and CVD in later life [4]. Thus, individuals in these regions have increased susceptibility to
cardiometabolic abnormalities at lower absolute levels
of adiposity. Indeed, this scenario is illustrated by the
INTERHEART study, a global case–control study which
highlighted the relevance of both atherogenic apolipoprotein (apo) B100-containing lipoproteins and potentially
atheroprotective apoA-I containing lipoproteins, such as
high-density lipoproteins (HDL), to coronary risk. The
population-attributable coronary risk due to dyslipidaemia
(defined as the ratio apoB/apoA-I) was almost double in
some of these emerging economic regions compared
with the European Union region (Figure 1) [5]. In
Latin America, abdominal obesity, dyslipidaemia and
smoking collectively accounted for 88% of the populationattributable coronary risk [6].
The Residual Risk Reduction Initiative (R3i) believes
that residual vascular risk represents a paramount public
health challenge in the 21st century [7]. Thus, the
mission of this worldwide, academic initiative is to
raise awareness of the numerous factors influencing residual vascular risk, with a focus on lipoprotein-related
risk factors, and to improve strategies for its therapeutic management. Five years ago, the R3i identified
atherogenic dyslipidaemia, defined as the imbalance
between proatherogenic apoB-containing lipoproteins
(contained in triglyceride-rich lipoproteins, TRLs) and
antiatherogenic apo A-I-lipoproteins (contained in HDL),
as a key contributor to residual CV risk [7]. This was
Page 2 of 17
supported by extensive evidence that both elevated
triglycerides and low HDL cholesterol were predictive
for CVD, independent of LDL cholesterol concentration.
Subsequent guidelines and expert consensus have recognised the importance of atherogenic dyslipidaemia as a
key driver of CV risk in insulin-resistant states, even if
LDL cholesterol levels are well controlled [8-12]. Thus,
targeting atherogenic dyslipidaemia secondary to LDL
cholesterol reduction has the potential for reducing
this risk. Five years on, the key question must be: Are
we closer to defining the optimal therapeutic strategy
for reducing lipid-related residual CV risk?
New insights: what is the relevance of HDL versus TRLs to
residual risk?
Emerging evidence provides new insight into the relative
importance of TRLs versus HDL cholesterol as a driver
of residual CV risk. Without doubt, the epidemiological
data for low HDL cholesterol as an important conditional
CV risk factor is robust, supported by evidence from the
Prospective Cardiovascular Münster (PROCAM) study,
and the Emerging Risk Factors Collaboration [13,14].
Furthermore, there is clear evidence from animal studies
that HDL-raising interventions inhibit the development of
atherosclerosis [15]. These data support the integration of
plasma HDL cholesterol concentration into the PROCAM
risk score and SCORE charts for CV risk assessment
[8,14,16]. However, it is acknowledged that the genetic
evidence in support of a protective role of HDL in humans
is more contentious. A recent analysis using a Mendelian
randomisation approach showed that lifelong exposure to
higher plasma levels of HDL cholesterol among carriers of
the loss-of-function endothelial lipase genetic variant
(LIPG Asn396Ser) did not translate to reduction in
myocardial infarction (MI) risk. Furthermore, there was
no association between an increase in HDL cholesterol
levels according to genetic score (based on 14 variants
associated with HDL cholesterol) and risk for MI,
whereas there was concordance for LDL cholesterol
[17]. These data appear to challenge the importance
of HDL cholesterol as a driver of residual CV risk, a
contribution further confounded by the presence of
different HDL subclasses.
However, we need to take a step back and consider
the relevance of HDL cholesterol concentration to the
atheroprotective capacity of HDL. Experimental studies
support a number of biological activities of HDL with
potential for atheroprotection [18]. Perhaps the most
important is the ability of HDL to promote cholesterol efflux from cells, including from macrophages in the arterial wall. As peripheral cholesterol efflux contributes less
than 5% of the cholesterol content of HDL, it would be reasonable to assume that HDL cholesterol concentration may
be a poor surrogate measure for estimating reverse
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Figure 1 Population-attributable coronary risk due to dyslipidaemia across different regions in the INTERHEART study [5]. Dyslipidaemia
was defined as the ratio of apolipoprotein B-containing lipoproteins to apolipoprotein A-I lipoproteins.
cholesterol transport, HDL function and CV risk [19]. A
preferable approach may involve measurement of the
concentration of specific HDL particle subclasses [20,21],
given evidence that these exhibit a number of biological
activities that might be relevant to the pathophysiology of
atherosclerosis. However, it is recognised that these are
static measurements that may not accurately reflect the
dynamic nature of HDL particle populations.
Latest thinking is that HDL functionality may be more
important than HDL quantity. Indeed, the relevance of
this approach is underlined by in vitro evidence that the
potential atheroprotective capacity of HDL is impaired
in certain disease states, including stable and unstable
coronary heart disease (CHD), as well as diabetes
[22-25]. In the latter setting, prolonged hyperglycaemia
has been associated with the formation of HDL that are
defective in anti-inflammatory activity [22]. Thus, from a
therapeutic perspective, improving the functionality of
HDL, as well as raising plasma HDL cholesterol levels,
might represent a more complementary approach.
However, our limited understanding of the complexity
of HDL particles, which are heterogeneous in terms
of origin, size, composition, structure and biological
function, has so far hampered efforts to define a suitable
marker of HDL functionality, let alone translate such
measures to the clinical setting. It is also a prerequisite
that functionality must parallel plasma concentration
of HDL in the general population, to explain the robust
association of HDL cholesterol levels with CV risk. However, every means of raising HDL cholesterol levels may
not necessarily increase HDL functionality.
There has also been re-evaluation of the importance of
TRLs as a driver of residual CV risk, especially in the
context of cardiometabolic disease. Evidence supports a
long-standing association between the level of triglycerides
(including nonfasting triglycerides), and CVD [26,27]. In
addition, genetic studies show that variants associated with
triglyceride-related pathways (for example the APOA5
variant 1131T>C), are associated with coronary risk
[28]. However, in the Emerging Risk Factors Collaboration
[13] the relationship between plasma triglycerides concentration and CVD was either attenuated or abolished after
adjusting for other risk factors. These conflicting data may
be explained by the view that triglycerides per se are not
atherogenic but instead represent a marker of CV risk
because of their association with atherogenic TRLs and
their remnants [10,29,30]. In fact, there is important
heterogeneity in TRL particles in terms of size, composition
and atherogenicity. Experimental studies have shown
that elevated plasma levels of TRLs and their remnants,
especially during the postprandial phase, accentuate
inflammatory responses, thereby increasing endothelial
dysfunction [29,30], and may act to suppress the atheroprotective and anti-inflammatory effects of HDL [31,32].
Elevated levels of TRL remnant cholesterol also contribute
directly to plaque formation and progression [33].
A recent study has provided evidence of a causal
association between remnant cholesterol contained in
TRLs and ischaemic heart disease [34]. A Mendelian
randomisation design was used to overcome confounding
between remnant cholesterol and other risk factors
including HDL, a major flaw in previous observational
studies [35,36]. The genes studied were those affecting
levels of HDL, LDL and triglycerides. In this study, a
1 mmol/L (39 mg/dL) increase in estimated levels of nonfasting remnant cholesterol (defined as total cholesterol –
[cholesterol in LDL and HDL]) was associated with a
2.8-fold causal risk for ischaemic heart disease; this
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was double the risk based on observational data alone
(hazard ratio 1.4, 95% confidence interval [CI] 1.3 to 1.5)
[34]. These findings imply that lifelong exposure to TRLs
through genetically elevated remnant cholesterol levels
may have a larger effect on coronary risk. In contrast,
there was no association between HDL cholesterol
concentration and risk for ischaemic heart disease
(Figure 2). However, it is not clear whether the data
would have been as strong if non-HDL triglycerides
(albeit more complicated to measure) had been used. Even
with this caveat, this study highlights the importance
of remnant cholesterol contained in TRLs as a key
contributor to residual CV risk.
In conclusion, given the metabolic interrelationships
between HDL and TRL-related pathways, and synergistic
effects on CV risk when both components of atherogenic
dyslipidaemia are present, even if LDL cholesterol is at
goal [37,38], the R3i believes that targeting both lipid
abnormalities is a key approach to reducing lipid-related
residual CVD risk. In this context, it is relevant that
the updated PROCAM risk score includes both HDL
cholesterol and triglycerides, a marker of TRLs, thereby
recognising the importance of both factors to residual
CV risk.
Assessment of residual CV risk
The previous mechanistic insights highlight the need
for lipid/lipoprotein targets that better reflect the burden of
atherogenic dyslipidaemia. Issues regarding the relevance of
HDL cholesterol concentration have already been raised,
but in the absence of validated data for HDL functionality,
no alternatives exist. In individuals with insulin-resistant
conditions and elevated triglycerides, current guidelines
and the recent International Atherosclerosis Society (IAS)
Position Paper recommend non-HDL cholesterol as
the preferred target [8,39]. By definition, non-HDL
cholesterol essentially represents the sum of cholesterol in
LDL cholesterol and very low-density lipoprotein (VLDL)
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cholesterol; the latter is regarded as increasingly important
as a driver of residual CV risk. Moreover, non-HDL
cholesterol can be measured in non-fasting serum.
Consistent with the IAS, the R3i strongly believes that
there should be renewed emphasis on the use of non-HDL
cholesterol as a key target for treatment decisions relating
to lipid-related residual CV risk.
An alternative approach may be to consider atherogenic
dyslipidaemia as a continuous variable using the ratio log
(triglycerides)/HDL cholesterol or log(triglycerides/HDL
cholesterol), based on fasting measures. In recent
studies this ratio was associated with a stepwise increase
in residual coronary risk, and was also predictive of poorer
metabolic control in people with type 2 diabetes [40-42].
However, taking into account the evidence base and
practical issues in lipid analysis, measurement of non-HDL
cholesterol is the simplest, most pragmatic target for
therapeutic strategies.
Targeting residual risk: current approaches
Lifestyle intervention underpins the management of atherogenic dyslipidaemia, as reinforced in recent guidelines [8].
However, it is recognised that long-term adherence to a
healthy lifestyle is frequently problematic. Additionally, even
among highly-motivated individuals, intensive therapeutic
lifestyle intervention may be insufficient to reduce CV risk.
Recent findings from the Look AHEAD trial illustrate this
[43]. Among obese/overweight individuals with type 2
diabetes, intensive lifestyle intervention involving both
dietary and physical activity measures, did not significantly
reduce major CV events beyond that observed with
diabetes support and education alone. It is, however,
acknowledged that intensive lifestyle intervention did
significantly impact atherogenic dyslipidaemia, on average
raising HDL cholesterol by ~5 mg/dL (0.13 mmol/L) and
reducing fasting triglycerides by ~30 mg/dL (0.34 mmol/L)
at the end of the 10-year study period. In addition, subjects
in the intensive lifestyle group had better control of diabetes
Figure 2 Remnant cholesterol, estimated indirectly as total cholesterol minus the cholesterol contents of LDL and HDL, was shown to
be causal for ischaemic heart disease, independent of HDL cholesterol. Reproduced with permission from Varbo et al. [34].
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and blood pressure than those in the comparator group,
despite reductions in their medications. These data clearly
provide justification for lifestyle intervention as the
first step for managing atherogenic dyslipidaemia, but
also indicate that most high-risk patients will also require
pharmacotherapy.
Current pharmacotherapeutic strategies
While definitive support for therapeutic options targeting
atherogenic dyslipidaemia to reduce residual CV risk is still
awaited, recent trials of fibrates, niacin (nicotinic acid),
omega-3 fatty acids and ezetimibe provide insights.
Fibrates Fibrates (peroxisome proliferator-activated
receptor-α [PPARα] agonists) represent one option,
especially in the context of high-risk individuals with
insulin-resistant conditions [44]. In subgroup analyses
of the FIELD (Fenofibrate Intervention and Event
Lowering in Diabetes) study, type 2 diabetes patients with
marked atherogenic dyslipidaemia, defined as triglycerides ≥204 mg/dL (2.3 mmol/L) and low HDL cholesterol,
obtained greater benefit from fenofibrate treatment than
those without this dyslipidaemia. In this group, which comprised 19% of the total study population, there was a 27%
relative reduction in CV risk (versus 11% in all patients)
[45]. Subsequently, in the ACCORD (Action to Control
Cardiovascular Risk in Diabetes) Lipid Trial (n = 5,518), a
pre-defined subgroup analysis indicated substantial
benefit associated with combining fenofibrate with
background simvastatin in type 2 diabetes patients with
marked atherogenic dyslipidaemia defined by baseline
triglycerides in the upper third of the population
(≥204 mg/dL or 2.3 mmol/L) and baseline HDL cholesterol
levels in the lower third (≤34 mg/dL or 0.9 mmol/L).
This group represented about 17% of the overall study
population. In these patients, there was ~30% relative
reduction in CV events versus no benefit in 83% of the
study population without this dyslipidaemia (Table 1) [46].
Furthermore, a meta-analysis of subgroups with similar
lipid criteria for atherogenic dyslipidaemia in the major
fibrate trials confirmed this benefit on residual CV risk
(Figure 3) [47]. Fibrate treatment was associated with a
35% relative reduction in CV risk in individuals with
atherogenic dyslipidaemia versus 6% in individuals
without this dyslipidaemia. A subsequent meta-analysis of
fibrate trials (n = 45,058) indicated that the reduction in
CV risk associated with this therapy class is predominantly
due to prevention of coronary events [48]. The observed
benefits of triglyceride-lowering on residual CV risk may
relate to the effects of endogenous pathways for PPARα
activation on atherosclerosis. Lipolysis in certain situations
can generate PPAR ligands and also limit some known
inflammatory responses [49]. Indeed, recent genome-wide
association studies show that gain of function variants of
Page 5 of 17
the lipoprotein lipase gene, coding for the enzyme which
hydrolyses the triglyceride core of plasma chylomicrons
and VLDL to release free fatty acids, are associated with a
decrease in plasma triglycerides and coronary risk [50].
An ancillary study of the ACCORD Lipid trial
(supported by the R3i), which evaluated effects on
postprandial lipaemia, provides a possible explanation as to why the benefit of fibrates is specific to
patients with atherogenic dyslipidaemia [51]. Compared with the simvastatin monotherapy group, treatment with the combination of fenofibrate plus
simvastatin led to significant reductions in postprandial exposure to triglycerides and apoB48, indicating a decrease
in the accumulation of atherogenic, intestinally-derived
TRL remnants. This effect of fenofibrate was selective
to patients with elevated fasting triglycerides at baseline.
Added to this, there is also evidence of benefit with fenofibrate on diabetes-related microvascular complications, including diabetic retinopathy and nephropathy [52-55].
Despite this favourable profile of macro- and microvascular benefits, the efficacy of the current fibrates may
be limited by uncertainties relating to the optimal level
of PPARα-agonism, agonist-specific biologic responses,
and the side effects of current synthetic agonists. Of
relevance for patients already on statin therapy, is the increased risk of muscle-related symptoms with the combination of a statin and certain fibrates, specifically
gemfibrozil. This does not appear to be an issue with
fenofibrate, probably due to the lack of interference of
fenofibrate on statin pharmacokinetics [8,56]. Indeed,
there was no adverse signal for myopathy in the ACCORD Lipid trial [44]. Other commonly reported adverse
effects include increases in homocysteine, creatinine and
liver enzymes, markers of CVD, renal disease and hepatic
dysfunction, respectively [46,54]. In the ACCORD Lipid
study, 48% of statin-treated patients who received the
full dose of fenofibrate (160 mg/day) for at least 30 days
before the 4-month follow-up showed >20% increase from
baseline in serum creatinine (versus 9% in the placebo
group) at this visit [57]. Both the ACCORD Lipid and the
FIELD studies subsequently showed that increases in
serum creatinine associated with fenofibrate were reversible, with levels returning to those observed in the placebo
group about 6–8 weeks after cessation of treatment, and
did not appear to detrimentally influence risk for CVD or
deterioration in renal function [58-60]. In the FIELD
study, despite increasing creatinine levels, fenofibrate
treatment was associated with less renal function decline,
as shown by a slower rate of loss of estimated glomerular
filtration rate over 5 years compared with placebo [59].
However, in high-risk older patients with impaired
renal function receiving multiple treatments likely to
affect renal haemodynamics, this may be a relevant
consideration.
Treatment/Trial [reference]
Daily dose (mg)
Patient criteria
Duration of follow-up Key findings
1601
Type 2 diabetes; Mean LDL-C ~2.07 mmol/L
4.7 years
[80 mg/dL] on simvastatin (mean dose 22.4 mg/day)
Fenofibrate
ACCORD Lipid (n = 5,518) [46]
• No significant benefit on any CV outcomes
for the total study population
• For patients with marked atherogenic
dyslipidaemia,2 there was ~30% reduction
in the primary CV outcome versus simvastatin
alone (12.4% versus 17.3%, p = 0.06 for
interaction versus all other patients)
Niacin
AIM-HIGH (n = 3,414) [61,62]
ER niacin titrating to 1500-2000 Patients with CVD with persistent atherogenic
dyslipidaemia3
Median LDL-C on statin 1.91 mmol/L
[74 mg/dL]
Prematurely terminated; • No significant outcomes benefit with ER niacin
mean 3 years
• Methodological issues; inadequately powered,
placebo contained a low-dose of niacin
(50 mg/capsule), imbalance in concomitant
LDL-C lowering therapy between groups
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Table 1 Recent trials investigating effects of fibrates, niacin or omega-3 fatty acids added to statin on residual cardiovascular risk
• For patients with marked atherogenic
dyslipidaemia,4 there was a 36% relative
reduction in the primary CV outcome
(25.0% versus 16.7%, p = 0.032)
HPS2-THRIVE (n = 25,673) [63]
ER niacin/laropiprant 2000
Patients with history of CVD
Median 3.9 years
Mean lipid values at end of pre-randomisation
phase (simvastatin 40 mg/day ± ezetimibe):
• No significant outcomes benefit with
ER niacin/laropiprant
• Significant increases in diabetic complications,
new-onset diabetes, infection, gastrointestinal
effects (p < 0.0001), musculoskeletal, bleeding
effects (p < 0.001) and skin adverse events
(p = 0.026) with ER niacin/laropiprant
LDL-C 1.64 mmol/L [63 mg/dL]
HDL-C 1.14 mmol/L [44 mg/dL]
TG 1.43 mmol/L [125 mg/dL]
Omega-3 fatty acids
JELIS (n = 18, 645) [65,66]
1800, EPA
High-risk patients with hypercholesterolaemia
(total cholesterol ≥6.5 mmol/L [250 mg/dL])
Mean 4.6 years
• 19% reduction in major coronary events
(2.8% versus 3.5%, p = 0.011) with EPA + statin
versus statin alone
• A post hoc analysis showed a 53% relative
reduction (p = 0.043) in patients with
TG ≥1.7 mmol/L (150 mg/dL) and HDL-C
<1.0 mmol/L (40 mg/dL) versus those without
this dyslipidaemia
40 months
• No significant effect on CV outcomes with any
treatment versus placebo (best evidence-based
treatment)
Baseline mean LDL-C 4.6 mmol/L [180 mg/dL]
on pravastatin 10 mg/day or simvastatin 5 mg/day
ALPHA-OMEGA (n = 4,837) [67] 400, EPA + DHA;
2 g ALA; or both
MI survivors, 85% on lipid-lowering therapy
(mainly statins)
Mean baseline lipids were
HDL-C 1.28 mmol/L [49.5 mg/dL]
Median TG 1.69 mmol/L [150 mg/dL]
Page 6 of 17
LDL-C 2.6 mmol/L [100 mg/dL]
ORIGIN
(n = 12,536) [68]
900 (465 EPA and 375 DHA)
Patients with or at risk of diabetes and at
high CV risk
Median 6.2 years
• No significant effect on primary outcome (CV death)
or secondary or other clinical outcomes
Mean baseline lipids were
TC 4.9 mmol/L (190 mg/dL)
LDL-C 2.89 mmol/L (112 mg/dL)
HDL-C 1.19 mmol/L (46 mg/dL)
Median TG 1.58 mmol/L (140 mg/dL)
1
Dose at start of trial, subsequently adjusted according to estimated glomerular filtration rate using the abbreviated Modification of Diet in Renal Disease equation; 2Marked atherogenic dyslipidaemia defined as
baseline triglycerides in the upper third of the population (≥204 mg/dL or 2.3 mmol/L) and baseline HDL cholesterol levels in the lower third (≤34 mg/dL or 0.9 mmol/L); 3Atherogenic dyslipidaemia defined as median
HDL-C 0.91 mmol/L [35 mg/dL] and median triglycerides 1.82 mmol/L [161 mg/dL]; 4Marked atherogenic dyslipidaemia defined as triglycerides >200 mg/dL or 2.3 mmol/L and HDL-C <32 mg/dL or 0.83 mmol/L.
ACCORD Action to Control Cardiovascular Risk In Diabetes; AIM-HIGH Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes; HPS2-THRIVE Heart
Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events; JELIS Japan Eicosapentaenoic acid Lipid Intervention Study; ORIGIN Outcome Reduction with an Initial Glargine Intervention; ALA
alpha-linolenic acid; CV cardiovascular; CVD cardiovascular disease; DHA docosahexaenoic acid EPA eicosapentaenoic acid; ER extended-release; HDL-C high-density lipoprotein cholesterol; LDL-C low-density
lipoprotein cholesterol; MI myocardial infarction; TC total cholesterol; TG triglycerides.
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Table 1 Recent trials investigating effects of fibrates, niacin or omega-3 fatty acids added to statin on residual cardiovascular risk (Continued)
Page 7 of 17
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Figure 3 Meta-analysis of major fibrate outcomes studies,
showing the impact of fibrate treatment on residual CV risk in
patients with atherogenic dyslipidaemia. An odds ratio <1
indicated a beneficial therapeutic effect. The two panels show data
from subgroups of patients with dyslipidaemia i.e., high levels of
triglycerides and low levels of high-density lipoprotein [HDL] cholesterol, Panel A; or from the complementary subgroups without this dyslipidaemia, Panel B. Subgroups with dyslipidaemia defined according
to the ACCORD Lipid trial (triglycerides ≥204 mg/dL or 2.3 mmol/L
and HDL cholesterol ≤34 mg/dL or 0.9 mmol/L) or closest to these
lipid criteria in each of the other trials were used in this analysis. The
outcome defined for each individual trial was used. A total of 2,428
fibrate-treated subjects (302 events) and 2,298 placebo-treated subjects
(408 events) with dyslipidaemia were included in the analysis reported
in A. Reproduced with permission from Sacks et al. [47].
Niacin Recent trials with niacin (nicotinic acid) have been
disappointing (Table 1). The AIM-HIGH (Atherothrombosis
Intervention in Metabolic Syndrome With Low HDL/High
Triglycerides: Impact on Global Health Outcomes) trial
(n = 3,414) [61] evaluated the effect of extended-release
(ER) niacin (1.5-2 g/day) on residual CV risk in patients
with CVD and optimally treated with a statin but
with residual atherogenic dyslipidaemia (median HDL
cholesterol 35 mg/dL or 0.91 mmol/L and median
fasting triglycerides 161 mg/dL or 1.82 mmol/L). The
Page 8 of 17
study was terminated 18 months earlier than planned
due to futility. A number of factors may explain the
lack of benefit. First, because of limited financial support,
the small study cohort required a very large effect size of
25% benefit for statistical significance. Second, the
trial design was flawed by the inclusion of a low dose
of niacin (50 mg/capsule) in the placebo, which may
have contributed to the 12% increase in HDL cholesterol
plasma concentration in the control group. Third, there
was imbalance in concomitant LDL lowering therapy
between the two groups; in the placebo group, 75% of
patients received simvastatin 40 mg/day or higher and 21%
also received add-on ezetimibe. Despite these limitations, a
subgroup analysis of AIM-HIGH in individuals with triglycerides >200 mg/dL (2.3 mmol/L) and HDL cholesterol
<32 mg/dL (0.83 mmol/L) showed a 36% relative reduction
(p = 0.032) in the primary composite end point, consistent
with findings from the fibrate meta-analysis [47,62].
More recently, the much larger HPS2-THRIVE (Heart
Protection Study 2-Treatment of HDL to Reduce the
Incidence of Vascular Events) (n = 25,673) [63] failed to
show a benefit on clinical outcomes with a different
niacin formulation (combined with laropiprant, which
attenuates the niacin flushing response). However, it should
be borne in mind that at baseline the HPS2-THRIVE
patient population had very well controlled LDL cholesterol
levels (mean 63 mg/dL or 1.64 mmol/L) and was outside of
the thresholds used to define atherogenic dyslipidaemia
(mean HDL cholesterol was 44 mg/dL or 1.14 mmol/L,
and triglycerides were 125 mg/dL or 1.43 mmol/L).
Consequently the trial did not test the effect of niacin
on residual CV risk due to atherogenic dyslipidaemia.
Moreover, there were safety issues with niacin/laropiprant,
notably significant increases in diabetes complications, newonset diabetes, infections, and gastrointestinal, musculoskeletal, bleeding and skin adverse events, leading
to subsequent world-wide withdrawal of this therapy
[64]. Niacin remains a therapeutic option in North
and South America, but is not an option in Europe
following suspension of niacin/laropiprant by the European
Medicines Agency.
Omega-3 fatty acids With respect to omega-3 fatty
acids, there were positive findings from JELIS (Japan
Eicosapentaenoic acid Lipid Intervention Study) (n = 18,645)
with the combination of omega-3 fatty acids (1.8 g/day
of eicosapentaenoic acid [EPA]) plus statin versus statin
alone, both overall and in patients with the metabolic
syndrome (Table 1) [65]. A post hoc analysis of JELIS
evaluated the effect of EPA treatment in individuals
with atherogenic dyslipidaemia as defined by triglycerides ≥150 mg/dL (1.7 mmol/L) and HDL cholesterol <40 mg/dL (1.0 mmol/L), representing 5% of the
total study population. In this dyslipidaemic group, EPA
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treatment reduced the risk of coronary artery disease by
53% (p = 0.043), compared with individuals without this
dyslipidaemia [66].
In contrast, the Alpha-Omega trial (n = 4,837) failed to
show a benefit on major CV events with the addition
of n−3 fatty acids (margarine containing EPA plus
docosahexaenoic acid with a targeted additional daily
intake of 400 mg) in patients with a previous MI receiving
best evidence-based antihypertensive, antithrombotic, and
lipid-modifying therapy (mainly statins) [67]. More recently,
the ORIGIN (Outcome Reduction with an Initial Glargine
Intervention) trial [68] used a 2x2 factorial design to
investigate the effect of treatment with omega-3 fatty
acids (1 g capsule containing ≥900 mg of ethyl esters
of n-3 fatty acids) versus placebo (one arm) and insulin
glargine versus standard care (second arm) in subjects
with or at high risk for diabetes and at increased CV
risk (n = 12,536). Treatment with n-3 fatty acids had
no significant effect on the primary outcome (CV death) or
any of the secondary or additional outcomes. It has been
suggested that the lack of effect may relate to the selected
dose, and/or extensive use of concomitant cardioprotective
treatments. Furthermore, a recent meta-analysis of trials of
omega-3 supplementation (n = 68,680 subjects in 20 trials,
mean dose 1.51 g/day) failed to show any significant
association with all-cause mortality, cardiac death,
sudden death, MI, or stroke [69]. There is also some
evidence from recent trials to suggest a possible link
between high plasma concentrations of omega-3 fatty
acids and increased risk of prostate cancer [70,71].
A new formulation of omega-3 fatty acids (AMR101, ≥96%
EPA ethyl ester) is being evaluated in the REDUCE-IT
trial in statin-treated patients with elevated trigycerides
(>1.7 mmol/L or 150 mg/dL) and at least one CV risk factor
[72]. However, results are not expected until 2017.
Page 9 of 17
combination of simvastatin plus ezetimibe did not result
in a significant difference in changes in intima-media
thickness compared with simvastatin alone in patients
with familial hypercholesterolaemia. This was despite
significant reductions from baseline in LDL cholesterol by
55% and triglycerides by 30%, and an increase in HDL
cholesterol by 10% in the combination therapy group [76].
It may be that treatment with ezetimibe for 2 years
is insufficient to differentiate significant incremental
clinical benefit, against a background of lipid-modifying
and pleiotropic effects of statin therapy. In support, while
partial ileal bypass surgery in POSCH (Program on the
Surgical Control of the Hyperlipidemia) and statin
treatment in 4S (Scandinavian Simvastatin Survival Study)
produced similar LDL cholesterol lowering (37.7% versus
35%), the separation of curves for CV outcomes of treated
versus non-treated subjects was evident after about 4.5 years
in POSCH but only 1.5 years in 4S [77,78]. However, the
possibility of pleiotropic effects with ezetimibe cannot be
discounted, on the basis of recent findings [79]. Results
from IMPROVE-IT (IMProved Reduction of Outcomes:
Vytorin Efficacy International Trial) [80] comparing
statin-ezetimibe combination therapy versus statin alone
against a background of best evidence-based treatment in
the acute coronary syndrome (ACS) setting are critical to
resolve this issue.
Do emerging therapies offer new hope?
While targeting atherogenic dyslipidaemia with the addition
of a fibrate or niacin may reduce residual CV risk in
statin-treated patients by about one-third, it is clear that
additional therapeutic options are also needed. Among
emerging therapies, there are a number of novel approaches
that may offer potential benefit (Table 2) [81-88].
Next generation PPAR agonists
Ezetimibe Combination therapy with statin plus ezetimibe
may represent an alternative approach to the management
of residual CV risk [10]. In a meta-analysis of 27 trials
(>21,000 patients), there was incremental lowering of LDL
cholesterol (by 15%), non-HDL cholesterol (by 13%)
and triglycerides (by 5%), and raising of HDL cholesterol
(by 1.6%) with the combination of ezetimibe plus statin
compared with statin alone [73]. However, so far there are
limited outcomes data to support this strategy. Although
there was significant reduction in major atherosclerotic
events (coronary death, MI, ischaemic stroke, or any revascularisation procedure) in patients with advanced renal
disease in SHARP (Study of Heart and Renal Protection),
SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) failed
to show significant clinical benefit in patients with aortic
stenosis [74,75]. Additionally, in the ENHANCE (Ezetimibe
and Simvastatin in Hypercholesterolemia Enhances
Atherosclerosis Regression) trial, treatment with the
One area of interest is the next generation of PPAR
agonists. There are three PPAR isoforms with different
pharmacological activities; PPARα plays a key role in lipid
metabolism, whereas PPARγ and PPARδ are critical
players in regulating energy metabolism in adipose tissue
and muscle, as well as being targets for the treatment of
insulin resistance. Thus, it was proposed that dual PPAR
agonists with selective activity for PPARα/γ or PPARα/δ
may offer opportunities to concomitantly manage several
areas of dysmetabolism, especially in the context of
cardiometabolic disease [89]. However, the recent termination of aleglitazar, a dual PPARα/γ agonist, due
to adverse safety signals and lack of efficacy based on
the recommendation of the Independent Data and Safety
Monitoring Board of the AleCardio (Aleglitazar in Patients
With a Recent Acute Coronary Syndrome and Type 2
Diabetes Mellitus) phase III trial is a disappointment
for this therapeutic class [90]. Previously, aleglitazar
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Page 10 of 17
Table 2 Emerging treatments with potential for targeting atherogenic dyslipidaemia
Effects on atherogenic
dyslipidaemia*
Treatment group/example
Dose
Other effects
Outstanding issues
Triglycerides
HDL-C
100 μg BID
↓70%
↑18%
Improved safety profile (CV, renal and
hepatic biomarkers) versus fenofibrate
● Outcomes data,
long-term safety
80 mg OD
↓17-25%
↑8-9%
Improved safety profile
(hepatic biomarkers)
● Lower efficacy than
current PPARα agonists
[reference]; duration
SPPARMs: K-877 [81]
12 weeks
Dual PPAR agonists
GFT505 (dual PPARα/δ) [84]
4 weeks
● Outcomes data,
long-term safety
CETP inhibitors
Anacetrapib1 [85]
100 mg OD
↓7%
↑138%
Decreases in LDL-C (~40%), Lp(a)
and apoB
● Outcomes data,
long-term safety
100 mg OD
NA
↑~80%
Decreases in LDL-C (36%); data on
other lipid effects NA
● Outcomes data,
long-term safety
150 mg every
2 weeks
↓19%
↑6%
Decreases in LDL-C (>60%); also Lp(a)
and apoB
● Outcomes data,
long-term safety
140 mg every
2 weeks
↓34%
↑8%
Decreases in LDL-C (>60%), Lp(a) and apoB
● Outcomes data,
long-term safety
24 weeks
Evacetrapib1 [86]
12 weeks
PCSK9 targeted therapy
Alirocumab1 [87]
12 weeks
AMG 1451,2 [88]
12 weeks
*Placebo-adjusted effect; 1Change from baseline in combination with a statin; 2AMG 145 is now referred to as evolocumab BID twice daily; apo apolipoprotein;
CETP cholesteryl ester transfer protein; CV cardiovascular; LDL-C low-density lipoprotein cholesterol; Lp(a) lipoprotein(a); NA not available; OD once daily; PCSK9
proprotein convertase subtilisin/kexin type 9; PPAR peroxisome proliferator-activated receptor; SPPARMs Selective peroxisome proliferator-activated receptor
modulators.
showed favourable effects on glucose homeostasis and
atherogenic dyslipidaemia in the phase II SYNCHRONY
trial in type 2 diabetes patients, although at all doses
(50 μg, 150 μg, 300 μg, or 600 μg once daily) there were
dose-dependent increases in body weight and the number
of patients developing oedema [82]. Saroglitazar is
currently the only agent of this class approved for the
treatment of type 2 diabetes (India, June 2013).
Dual PPARα/δ agonists are also under investigation; the
most advanced in development is GFT505, which has
preferential activity on PPARα [89]. In a phase II trial in
patients with combined dyslipidaemia or prediabetes,
GFT505 improved glucose homeostasis, reduced triglycerides and LDL cholesterol, and raised HDL cholesterol
levels [84,91]. GFT505 also reduced liver enzymes,
suggesting potential for the management of individuals
with prediabetes and non-alcoholic fatty liver disease [91].
In addition, K-877, a highly potent and selective PPARα
modulator (SPPARM), is undergoing phase II/III development for the management of atherogenic dyslipidaemia.
Mechanistically, K-877 offers advantages over fenofibrate in
terms of increased PPARα potency and improved PPAR
safety profile (CV, renal and hepatic biomarkers) [89]. In a
phase II trial, K-877 showed improved lipid-modifying
efficacy and greater effects on postprandial lipaemia
compared with fenofibrate, in particular suppressing
the postprandial increase in triglycerides and atherogenic
intestinal (apoB48) remnant cholesterol [81,92,93]. There
was also evidence suggestive of an improved safety profile
with K-877 over fenofibrate [81].
Cholesteryl ester transfer protein (CETP) inhibitors
Cholesteryl ester transfer protein (CETP) inhibition has
also attracted attention as a therapeutic approach. CETP
has a critical role in the intravascular mass transfer and
heteroexchange of cholesteryl ester and triglycerides
between HDL and TRL and their remnants in vivo. Thus,
CETP inhibition may be anti-atherogenic by increasing
the concentration of cholesterol in the HDL fraction, and/or
by decreasing LDL or the cholesterol content of TRL. There
have been issues with the first two CETP inhibitors,
torcetrapib and dalcetrapib. The former was terminated
due to safety issues in ILLUMINATE (Investigation of
Lipid Level Management to Understand Its Impact in
Atherosclerotic Events), probably due to off-target effects
on blood pressure and/or the artery wall [94,95]. In
contrast, dalcetrapib was terminated due to futility in
dal-OUTCOMES in ACS patients. The reason for this
is uncertain, but may relate to the patient population,
given the lack of association between baseline HDL
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cholesterol and the risk of incident CV events observed in
the placebo group [96].
The two CETP inhibitors that are currently most
advanced in development, anacetrapib and evacetrapib,
have so far shown no adverse safety signal in phase II
trials, and have beneficial effects in raising HDL cholesterol,
as well as lowering triglycerides and atherogenic lipoproteins including LDL cholesterol and lipoprotein(a) [85,86].
Both agents are now under study in major prospective
outcomes studies – REVEAL (Randomized EValuation of
the Effects of Anacetrapib Through Lipid-modification) with
anacetrapib and ACCELERATE (A Study of Evacetrapib in
High-Risk Vascular Disease) with evacetrapib – to evaluate
whether their lipid-modifying effects translate to reduction
in CV risk beyond that observed with LDL cholesterol
lowering with a statin [97,98].
PCSK9-targeted therapy
There is considerable interest in novel therapy targeting
proprotein convertase subtilisin/kexin type 9 (PCSK9),
which has a pivotal role in promoting degradation of hepatic LDL receptors, and hence in LDL homeostasis. Thus,
inhibition of PCSK9 prevents LDL receptor degradation
and offers the possibility of lowering LDL cholesterol levels,
a rationale which is now supported by clinical trials [99].
Indeed, monoclonal antibody therapy targeting PCSK9
holds promise. Both of the most advanced therapies,
alirocumab and evolocumab (AMG 145), have been
shown to improve attainment of LDL cholesterol goals
in high-risk statin-treated patients, and have beneficial
effects on other lipids, including lowering atherogenic
TRLs and lipoprotein(a), and modestly raising HDL
cholesterol [87,88]. Although these trials have been relatively short-term to date, there is no evidence yet to suggest
any significant adverse signal. Major phase III prospective
trials are now in progress to assess their long-term safety
and effects on residual CV risk in high-risk statin-treated
patients [100,101].
ApoA-I therapies
Finally, the development of novel apoA-I therapies
may have potential application in managing residual
CV risk in the ACS setting. The rationale for this approach
is supported by evidence of reduction in coronary
atherosclerosis in ACS patients following infusion of
recombinant apoA-IMilano [102]. In experimental models,
recent apoA-I mimetics were shown to have atheroprotective effects, including anti-inflammatory properties
[103]. In phase I studies, infusion of CSL112, a novel
formulation of reconstituted apoA-I, improved prebeta1HDL, as well as global cholesterol efflux capacity from
macrophages, and had strong anti-inflammatory activity
[104]; this agent is now in phase II development. RVX-208,
which acts via an epigenetic mechanism to increase apoA-I
Page 11 of 17
synthesis, did not meet its primary outcome (0.6% change
in percent atheroma volume) in the ASSURE (ApoA-I
Synthesis Stimulation and Intravascular Ultrasound
for Coronary Atheroma Regression Evaluation) trial in
patients with angiographic evidence of CHD and low
HDL cholesterol [105]. It is recognised that these agents
are at an early stage of development and have not been
tested in outcomes studies in ACS patients.
Conclusion: looking to the future for residual CV risk
The management of residual CV risk is a major challenge
for the 21st century, compounded by the escalating
pandemics of obesity, metabolic syndrome and type 2
diabetes. As discussed, atherogenic dyslipidaemia – the
combination of elevated TRLs and their remnants and low
HDL – is an important modifiable contributor to residual
CV risk. There is general consensus regarding the
importance of atherogenic dyslipidaemia as a key
driver of CV risk in individuals with cardiometabolic
disease [8,12]. However, the recently published American
College of Cardiology/American Heart Association
(ACC/AHA) Guidelines on the Treatment of Blood
Cholesterol [106] solely focus on statins for CVD prevention, and omit consideration of other therapies for
management of residual CV risk in high-risk patients
with persistent atherogenic dyslipidaemia despite being at
LDL cholesterol goal. In the context of the escalating
burden of obesity and type 2 diabetes, the ACC/AHA
guidelines are clearly an oversimplification of dyslipidaemia management. Given that these guidelines ignore both
the strength and congruence of the evidence from clinical
and mechanistic studies for atherogenic dyslipidaemia,
it is not surprising that both the US National Lipid
Association and the American Association of Clinical
Endocrinologists have failed to endorse the new ACC/AHA
guidelines [107,108]. The European Atherosclerosis
Society (EAS) also reaffirms that the European Society of
Cardiology/EAS guidelines for management of dyslipidaemia are more appropriate in Europe [109].
Yet even where evidence-based guidelines recognise
and incorporate management strategies for atherogenic
dyslipidaemia, there is still lack of awareness in routine
practice. For example, the Dyslipidemia International
Study (DYSIS) in 22,063 statin-treated outpatients in
Europe and North America showed that the prevalence
of elevated triglycerides and/or low HDL cholesterol was
highest (exceeding 40%) in high-risk individuals [110].
Clearly there is an urgent need for action to address this
unmet challenge.
As part of its mission to improve the awareness and
clinical management of atherogenic dyslipidaemia to reduce residual CV risk, the R3i highlights a number of
priorities. The R3i issues four recommendations: (i)
education is needed to improve awareness of
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atherogenic dyslipidaemia as a key driver of lipidrelated residual cardiovascular risk, especially in highrisk patients with insulin-resistant conditions; (ii)
non-HDL cholesterol is the preferred target for treatment decisions relating to atherogenic dyslipidaemia;
(iii) the addition of a fibrate, niacin (North and South
America), omega-3 fatty acids or ezetimibe to statin
therapy are approaches to reduce non-HDL cholesterol. Post hoc analyses indicate that addition of a
fibrate or niacin can reduce residual CV risk by about
one-third in high-risk statin-treated patients with
atherogenic dyslipidaemia; and (iv). Additional approaches are clearly needed; results from on-going trials
with novel agents are awaited.
As discussed, the R3i believes that monitoring of nonHDL cholesterol will provide a simple, practical tool for
treatment decisions relating to lipid-related residual CV
risk. However, evidence from the US National Health and
Nutrition Examination Survey 2002–2010 shows that
despite guidelines and the availability and use of effective lipid-modifying therapy, there has been little
discernible improvement in non-HDL cholesterol goal
attainment among patients with atherogenic dyslipidaemia. Of those with triglycerides > 200 mg/dL (2.3 mmol/L)
only 13% had a non-HDL cholesterol level <130 mg/dL
(3.4 mmol/L). Furthermore, over 60% had a high to very
high non-HDL cholesterol level (>160 mg/dL or
4.1 mmol/L) [111]. Education is clearly needed to improve
the implementation of guideline-based dyslipidaemia
management.
The R3i recognises that current evidence relating to
the treatment of residual atherogenic dyslipidaemia is
somewhat limited. Consistent with the IAS position
statement [39], the R3i recommends addition of a fibrate,
niacin (North and South America), omega-3 fatty acids
or ezetimibe as options for combination with a statin to
reduce non-HDL cholesterol.
The future holds promise. Several emerging treatments may offer potential, although benefit versus risk
analysis, especially in the longer-term, requires further
consideration. The R3i awaits the results of major ongoing trials with these novel agents which may help to
define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden
of residual CV risk.
Abbreviations
ACC/AHA: American College of Cardiology/American Heart Association;
ACS: Acute coronary syndrome; Apo: Apolipoprotein; CETP: Cholesteryl ester
transfer protein; CHD: Coronary heart disease; CI: Confidence interval;
CV: Cardiovascular; CVD: Cardiovascular disease; EAS: European
Atherosclerosis Society; EPA: Eicosapentaenoic acid; ER: Extended-release;
HDL: High-density lipoprotein; IAS: International Atherosclerosis Society;
LDL: Low-density lipoprotein; MI: Myocardial infarction; PCSK9: Proprotein
convertase subtilisin/kexin type 9; PPAR: Peroxisome proliferator-activated
receptor; R3i: Residual Risk Reduction Initiative; SPPARM: Selective peroxisome
proliferator-activated receptor modulator; TRL: Triglyceride-rich lipoprotein;
Page 12 of 17
VLDL: Very low-density lipoprotein; ACCELERATE: A study of evacetrapib in
high-risk vascular disease; ACCORD: Action to Control Cardiovascular Risk in
Diabetes; AIM-HIGH: Atherothrombosis Intervention in Metabolic Syndrome
with low HDL/high triglycerides: Impact on Global Health Outcomes;
AleCardio: Aleglitazar in patients with a recent acute coronary syndrome and
type 2 diabetes mellitus; ASSURE: ApoA-I Synthesis Stimulation and
Intravascular Ultrasound for Coronary Atheroma Regression Evaluation;
DYSIS: Dyslipidemia International Study; ENHANCE: Ezetimibe and
Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression;
FIELD: Fenofibrate Intervention and Event Lowering in Diabetes;
HPS2-THRIVE: Heart Protection Study 2-Treatment of HDL to Reduce the
Incidence of Vascular Events; ILLUMINATE: Investigation of Lipid Level
Management to Understand its Impact in Atherosclerotic Events;
IMPROVE-IT: IMProved Reduction of Outcomes: Vytorin Efficacy
International Trial; JELIS: Japan Eicosapentaenoic acid Lipid Intervention
Study; ORIGIN: Outcome Reduction with an Initial Glargine Intervention;
POSCH: Program on the Surgical Control of the Hyperlipidemia;
PROCAM: Prospective Cardiovascular Münster Study; REVEAL: Randomized
Evaluation of the Effects of Anacetrapib through Lipid-modification;
4S: Scandinavian Simvastatin Survival Study; SEAS: Simvastatin and
Ezetimibe in Aortic Stenosis; SHARP: Study of Heart and Renal Protection.
Competing interests
P Amarenco (PA) has received research grants from Pfizer, Sanofi,
Bristol-Myers-Squibb, Merck, AstraZeneca, Boehringer Ingelheim and the
French government; and honoraria for lectures/consultancy from Pfizer,
Sanofi, Bristol-Myers-Squibb, Merck, AstraZeneca, Boehringer Ingelheim,
Bayer, Daiichi Sankyo, Lundbeck, Edwards, Boston Scientific, Kowa, and
St-Jude Medical.
P Barter (PB) has received research grants from Merck and Pfizer; honoraria
for consulting from Amgen, AstraZeneca, ISIS, Kowa, Merck, Novartis, Pfizer
and Roche; and honoraria as a member of Advisory Boards from
AstraZeneca, CSL, Kowa, Lilly, Merck, Novartis, Pfizer and Roche.
J Betteridge (JB) has received honoraria for advisory boards and lectures
from MSD, Pfizer, AstraZeneca, Kowa, Janssen, Amgen, Takeda and Sanofi.
E Bruckert (EB) has received research funding from GlaxoSmithKline, MSD,
Genzyme, Sanofi, Aegerion and Montreal University; and honoraria for
consulting/presentation from AstraZeneca, Genfit, Genzyme, MSD, Pfizer,
Sanofi, Servier, AMT, Merck, Lilly, Novo-Nordisk, Pfizer and Aegerion.
A Cuevas (AC) has served on advisory boards for MSD and Amgen, and has
received honoraria for lectures from MSD and Sanofi.
J Davignon (JD) has received honoraria for consultancy or as a scientific
advisor for Abbott (Solvay), Acasti Pharma, Amgen, AstraZeneca, Anthera,
Genzyme, McCain, Merck, Pfizer, Pharmena (Cortria), Sanofi-Regeneron,
Roche and Valeant; and for participation in clinical trials for Amgen, Cortria,
Genzyme, Merck, Pfizer and Sanofi-Regeneron. He has also received
honoraria as a member of the Speakers bureau for the International
Atherosclerosis Society. He is a Board Member for the Consortium Québecois
sur la Découverte du Médicament (CQDM), and the Residual Risk Reduction
Initiative Foundation.
E Ferrannini (EF) has received honoraria for speakers bureau/advisory
boards from MSD, Halozyme, GlaxoSmithKline, Bristol-Myers-Squibb,
AstraZeneca, Eli Lilly & Co., Novartis, Daiichi Sankyo and Sanofi. He has
received research grant support from Eli Lilly & Co., and Boehringer
Ingelheim.
M Farnier (MF) has received grants, consulting fees and/or honoraria for
lectures for Abbott, Amgen, Boehringer Ingelheim, Genzyme, Kowa, Merck and
Co., Novartis, Pfizer, Recordati, Roche, Sanofi-Aventis and Bristol-Myers-Squibb.
P Fioretto (PF) has received honoraria for lectures from Abbott,
Bristol-Myers-Squibb, AstraZeneca, Boehringer and Lilly.
J-C Fruchart (JCF) has received honoraria as a consultant for SMB
laboratories, McCain and Kowa Co. Ltd. He is President of the Residual Risk
Reduction Initiative.
J Genest (JG) has received research funding from Amgen, Lilly and Merck
and honoraria as a member of Speaker’s bureau/advisory boards from Merck,
Amgen, Sanofi and Aegerion.
HN Ginsberg (HNG) has received research funds from Sanofi-Regeneron,
Amgen, Sanofi-Genzyme, Merck and consulting honoraria from
Sanofi-Regeneron, Amgen, Sanofi-Genzyme, Merck, Bristol-Myers-Squibb,
AstraZeneca, Pfizer, Kowa, Janssen and Boehringer Ingelheim.
Fruchart et al. Cardiovascular Diabetology 2014, 13:26
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AM Gotto (AMG) is on the board of Directors for Aegerion and Arisaph; has
been a consultant for AstraZeneca, Janssen, Kowa, Merck, Pfizer and Roche;
and has served on advisory boards for DuPont and Vatera Capital.
MP Hermans (MPH) has served on an advisory panel and/or received
speaker’s honoraria or travel/research grants from Abbott, Amgen,
AstraZeneca, Boehringer, Bristol-Myers-Squibb, Boehringer Ingelheim,
GlaxoSmithKline, Janssen, Eli Lilly, LifeScan, Menarini, Merck, Novartis, Novo
Nordisk, Roche, Sanofi and Takeda.
T Kodama (TK) has received honoraria as a consultant and research funding
from Kowa Co.Ltd.
M Kremp (MK) has received honoraria for lectures from AstraZeneca, MSD,
Bristol-Myers-Squibb and Sanofi.
J Millan Núñez-Cortés (JMN-C) has received honoraria as a member of
advisory boards from Abbott, AstraZeneca, MSD, Pfizer and Sanofi; and for
educational activities from Abbott, AstraZeneca and MSD.
H Ogawa (HO) has received honoraria for consulting from Amgen,
GlaxoSmithKline and Novartis; and honoraria for lectures from AstraZeneca,
Bayer, Boehringer lngelheim, Daiichi Sankyo, Mitsubishi Tanabe, MSD, Sanofi
and Takeda. He has received research/scholarship grants from Bayer, Daiichi
Sankyo, AstraZeneca, Astellas, Takeda, Mitsubishi Tanabe, Boehringer
lngelheim and MSD.
J Plutzky (JP) has received research grants from GlaxoSmithKline and
Bristol-Myers-Squibb; and honoraria for consultancy from Amylin
Pharmaceuticals, AstraZeneca, Bristol-Myers-Squibb, Genzyme,
GlaxoSmithKline, Eli Lilly, Janssen, Mesoblast, Merck, NovoNordisk, Pfizer,
Roche/Genentech, Takeda and Vivus.
DJ Rader (DJR) has received honoraria for consulting from Merck, Pfizer, Eli
Lilly, Sanofi, Amgen, Novartis, Omthera, Aegerion and CSL.
RD Santos (RDS) has received honoraria for consulting and/or speaking from
AstraZeneca, Abbott, Biolab, Merck, Bristol-Myers-Squibb, Roche, Pfizer,
Amgen, Aegerion, Boehringer Ingelheim, Sanofi, Genzyme and Nestle.
A Tall (AT) has received honoraria for lectures and advisory boards from
MSD, Eli Lilly, Roche, Amgen, Arisaph and CSL.
L Tokgözoğlu (LT) has received honoraria for lectures and advisory boards
from Abbott, Actelion, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi
Sankyo, Kowa, MSD, Novartis, Pfizer, Roche, Sanofi and Servier.
PP Toth (PPT) has received honoraria as a member of speakers bureau for
Amarin, AstraZeneca, GlaxoSmithKline, Kowa, Merck; and for consultancy for
Amgen, AstraZeneca, Atherotech, Boehringer Ingelheim, Kowa, Liposcience
and Merck.
P Valensi (PV) has given lectures and/or been a consultant for Abbott, MSD
and Kowa.
C Wanner (CW) has received honoraria for lectures and travel support from
Astellas, Merck and Pfizer.
A Zambon (AZ) has received speaker honoraria from Abbott, AstraZeneca,
Roche and Amgen.
P Zimmet (PZ) has received travel funding from Fournier.
K Al-Rubeaan (KA-R), G Assmann (GA), Y Matsuzawa (YM), C Calvo Monfil
(CCM), D Hu (DH),T Kadowaki (TK), S Sadikot (SS), E Shlyakhto (ES), P Sritara
(PS), R Sy (RS), CE Tan (CET) and J Zhu (JZ) report no competing interests.
Authors’ contributions
JCF, JD and MPH prepared the initial draft of the manuscript; GA also
provided data relating to the PROCAM study. All authors critically reviewed
the paper, were involved in revisions of the manuscript, and read and
approved the final manuscript.
Authors’ information
The Residual Risk Reduction Initiative (http://www.r3i.org) is an international,
academic, multidisciplinary non-profit organization which is focused on addressing the high residual risk of macrovascular and microvascular
complications in patients with atherogenic dyslipidaemia.
G Assmann is also chairman of the Assmann Foundation for Prevention.
Acknowledgements
There are no sources of funding for this paper.
Author details
1
R3i Foundation, St. Alban-Anlage 46, Basel, CH 4010, Switzerland. 2Fondation
Cœur et Artères, Lille, France. 3Institut de recherches cliniques de Montréal;
Centre Hospitalier de l’Université de Montréal and Department of
Page 13 of 17
Experimental Medicine, McGill University, Montreal, Canada. 4Cliniques
Universitaires Saint-Luc, Brussels, Belgium. 5University Diabetes Center, King
Saud University, Riyadh, Saudi Arabia. 6Department of Neurology and Stroke
Centre, Bichat University Hospital, Paris, France. 7Assmann-Stiftung für
Prävention, Münster, Germany. 8Centre for Vascular Research, University of
New South Wales, Sydney, Australia. 9University College London, London, UK.
10
Department of Endocrinology and Cardiovascular Disease Prevention,
Institut of CardioMetabolism and Nutrition (ICAN) Hôpital Pitié-Salpêtrière,
Paris, France. 11Nutrition Center, Clínica Las Condes, Santiago, Chile. 12Point
Medical, Dijon, France. 13University of Pisa School of Medicine, and
Metabolism Unit of the National Research Council (CNR) Institute of Clinical
Physiology, Pisa, Italy. 14Department of Medical and Surgical Sciences,
University of Padova, Padova, Italy. 15McGill University and Center for
Innovative Medicine, McGill University Health Center/Royal Victoria Hospital,
Montreal, Canada. 16Department of Medicine and Irving Institute for Clinical
and Translational Research, Columbia University, New York, USA. 17Weill
Cornell Medical College, Cornell University, New York, USA. 18Heart Institute,
People Hospital of Peking University, Beijing, China. 19Department of
Diabetes and Metabolic Diseases Unit, The University of Tokyo, Tokyo, Japan.
20
Department of Systems Biology and Medicine, The University of Tokyo,
Tokyo, Japan. 21Human Nutritional Research Center and Department of
Endocrinology, Metabolic Diseases and Nutrition, University Hospital Nantes,
Nantes, France. 22Sumitomo Hospital and Osaka University, Osaka, Japan.
23
University Hospital Gregorio Marañón, Universidad Complutense, Madrid,
Spain. 24University of Concepción, Concepción, Chile. 25Department of
Cardiovascular Medicine, Kumamoto University, Kumamoto, Japan. 26Brigham
and Women’s Hospital and Harvard Medical School, Boston, USA. 27Division
of Translational Medicine and Human Genetics, Smilow Center for
Translational Research, Penn Cardiovascular Institute, Philadelphia, PA, USA.
28
Jaslok Hospital and Research Center, Mumbai, India. 29Unidade Clínica de
Lipides InCor-HCFMUSP, Sao Paulo, Brazil. 30Federal Almazov Heart Blood
Endocrinology Centre, St Petersburg, Russia. 31Mahidol University, Bangkok,
Thailand. 32University of the Philippines-Philippine General Hospital, Manila,
The Philippines. 33Specialized Center of Research (SCOR) in Molecular
Medicine and Atherosclerosis, Columbia University, College of Physicians &
Surgeons, New York, USA. 34Gleneagles Medical Centre, Singapore.
35
Hacettepe University, Ankara, Turkey. 36Sterling Rock Falls Clinic, CGH
Medical Center, Sterling and University of Illinois School of Medicine, Peoria,
IL, USA. 37Hôpital Jean Verdier, Department of Endocrinology Diabetology
Nutrition, AP-HP, Paris-Nord University, CRNH-IdF, CINFO, Bondy, France.
38
University Hospital Würzburg, Würzburg, Germany. 39Zhongshan Hospital,
Fudan University, Shanghai, China. 40Baker IDI Heart and Diabetes Institute,
Melbourne, Australia.
Received: 7 November 2013 Accepted: 7 December 2013
Published: 24 January 2014
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Cite this article as: Fruchart et al.: Residual macrovascular risk in 2013:
what have we learned? Cardiovascular Diabetology 2014 13:26.
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