New Insights Link Low HDL-Cholesterol and Elevated Triglycerides With Coronary Heart Disease and Microvascular Complications in Patients at Goal for LDL-Cholesterol
– Surveys Establish Residual Vascular Risk is Associated With Atherogenic
Dyslipidemia Suggesting the Need to Reconsider Approach to Management of
Lipids
– Residual Risk Reduction initiative (R3i) Foundation Presents Early
Findings From Unique Global Investigation Into Effects on Residual
Macrovascular and Microvascular Risk
Low levels of high-density lipoprotein cholesterol (HDL-C) and raised
triglycerides, affecting millions of patients worldwide, are strongly linked
to significantly increased risk of coronary heart disease (CHD) even in
patients who achieve or surpass current low density lipoprotein cholesterol
(LDL-C) targets.
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This has been demonstrated in new analyses of the landmark Prospective
Cardiovascular Munster (PROCAM) and the REsiduAl risk Lipids and Standard
Therapies (REALIST) surveys, the latter funded and conducted by the Residual
Risk Reduction Initiative Foundation or R3i. These data have been presented
today at the European Society of Cardiology (ESC) congress.
The final objective of the R3i is to significantly reduce the incidence
of both major macrovascular events and microvascular complications (e.g. in
patients with type 2 diabetes or affected by the metabolic syndrome) beyond
what is already achieved with current treatments.[1],[2]
Earlier studies, largely conducted in patients treated with statins show
that lowering LDL-C to currently recognized goals only reduces the relative
risk of macrovascular disease by about 23 percent.[3]
“The residual vascular risk driven by the increasing epidemic of obesity,
metabolic syndrome and type 2 diabetes is not being adequately treated by
clinicians,” stated Professor
current target, we have taken LDL-C reduction to its therapeutic limits
without abolishing CVD events. Therefore we urgently need new strategies to
address other modifiable risk factors such as atherogenic dyslipidemia.”
New insights into lipid-related macrovascular risk
Professor
Committee and President of the Board of the Assmann-Foundation for
Prevention, presented a new analysis from PROCAM in which 823 men who
survived a myocardial infarction (MI) were matched with an equal number of
controls free from MI. This analysis, which was funded by the R3i,
demonstrated:
- Low HDL-C and/or elevated triglycerides (TG) was seen in
nearly two-thirds of MI patients
- When all risks factors were matched, the odds of experiencing a MI were
increased five-fold for men with LDL-C at target (less than or equal to
100mg/dL) presenting a low level of HDL-C (<45 mg/dL) and an elevated
level of TG (>150 mg/dL)
The initial macrovascular findings of REALIST were also presented by
Professor
conducted in 170 patients hospitalized with CHD in
LDL-C, matched with 175 controls free from CHD shows that:
- High TG and low HDL-C are strong indicators of residual risk of CHD
- High TG and low HDL-C levels each contribute to the risk of a coronary
event in patients with LDL-C levels less than or equal to 130 mg/dL or
even less than or equal to 70 mg/dL
- TG and HDL-C appear to act synergistically with the impact of TG
increasing when HDL-C is low and the impact of HDL-C increasing when TG
levels are high
- When moving from the lowest levels of TG and highest levels of HDL-C to
the highest levels of TG and lowest levels of HDL-C, the risk of CHD
increases 10-fold
Addressing atherogenic dyslipidemia may reduce the microvascular
complications of type 2 diabetes
REALIST is also evaluating the risk of microvascular complications in
patients with type 2 diabetes who achieve or approach LDL-C goal. Data
collected by Professor
Saint-Luc in
from the Department of Medical and Surgical Sciences, University of Padua,
- Low HDL-C, elevated TG and elevated non-HDL-C levels are more
prevalent in patients who developed microvascular complications
- High TG levels are associated with increased risk of incident
retinopathy, blindness and diabetic kidney disease
- Low HDL-C levels are associated with incident diabetic kidney
disease
Similar to the findings of the macrovascular REALIST survey, the initial
microvascular data showed that patients with incident microvascular
complications of type 2 diabetes are more likely to present with atherogenic
dyslipidemia even when LDL-C is nearly at goal (less than or equal to
130mg/dL).
“Further analysis of microvascular data from this and other centers
should confirm the relationship between atherogenic dyslipidemia and
microvascular complications of type 2 diabetes,” said Professor Fioretto.
Implications of the R3i research program for future treatment
The REALIST research program is being globally extended and data are
currently being collected in 27 centers in 12 countries around the world.
This will support the major global program of education and advocacy being
implemented by the R3i.
The ultimate objective of the R3i Foundation is to identify new
indicators of macro- and microvascular residual risk as targets for future
treatment strategies.
Residual vascular risk – A public health emergency
“Further reduction of LDL-C by use of the maximum permissible statin
dosage is unlikely to be able to substantially lower this residual, largely
non-LDL-C mediated risk,” says Professor
Munster,
Therefore, while statins are effective, other treatment strategies are
urgently needed to address the residual vascular risk which persists in
patients despite current standards of care. While the R3i research program
will help define appropriate targets for intervention in patients who remain
at high residual vascular risk, the ongoing outcomes trials such as ACCORD,
AIM-HIGH and HPS2-THRIVE will help determine new treatment strategies to
address this risk.
“The R3i has a huge task ahead to get people recognizing the threat of
residual vascular risk and acting to better manage it,” said Professor
R3i. “We have to look beyond using statins as a silver bullet to reduce
LDL-cholesterol. The mindset that reducing one component to prevent heart
disease is wrong and needs to change.”
Notes to Editors
More information on the R3i is available from:
The R3i website: http://www.r3i.org
Epidemiological study methods
The PROCAM analysis used a case-control approach in which 823 men who had
survived a MI were matched with an equal number of controls. Patients, who
were matched for age, smoking status, type 2 diabetes status, blood pressure
and LDL-C to an equal number of MI-free controls from the PROCAM cohort of
50,000 participants, a unique prospective investigation of coronary artery
disease (CAD) and stroke risk factors in
The macrovascular REALIST survey was designed to determine, in patients
at goal for LDL-C (less than or equal to 130 mg/dL whether treated or
untreated for elevated LDL-C) with a first or subsequent coronary event,
whether low HDL-C and/or elevated TG levels are associated with a significant
risk of coronary event after adjustment for other risk factors. Adult male or
female patients admitted to coronary care units (CCUs) or explored in cardiac
catheter laboratories were matched with controls hospitalized for other
reasons.
The microvascular REALIST survey was designed to determine whether low
HDL-C and/or elevated TG levels are associated with a significant residual
risk of microvascular complications. Data will be adjusted for other risk
factors such as age, gender, diabetes duration, HbA1C, LDL-C levels, blood
pressure, BMI and smoking status in patients with type 2 diabetes nearly at
goal for LDL-C and presenting with incident microvascular complication
(retinopathy, maculopathy or nephropathy). Diabetic neuropathy is an
exploratory disease due to difficulties in establishing it with certainty in
retrospective analysis. The REALIST surveys are currently being conducted in
What is residual vascular risk?
Residual vascular risk is defined as the significant residual risk of
macrovascular events and microvascular complications which persists in most
patients despite current standards of care including achievement of
low-density lipoprotein (LDL-C) goal and intensive control of blood pressure
and blood glucose.
Although statin therapy is the cornerstone of dyslipidemia management,
LDL-C lowering with statins reduces the risk of major coronary events by
approximately one-quarter, with 77 percent of the relative risk of events
still occurring.[3]
Multifactorial intensive therapy (including statins) is insufficient to
prevent the development or progression of microvascular disease (retinopathy,
nephropathy, neuropathy) in up to 50 percent of patients with type 2
diabetes.[4]
Atherogenic Dyslipidemia and Residual Vascular Risk
Atherogenic dyslipidemia is characterized by elevated TG and low levels
of HDL-C.
In the past three decades in the U.S., while the prevalence of abnormal
levels of LDL-C has decreased, the prevalence of combined abnormal TG
(greater than or equal to 150 mg/dL) and HDL-C (<40 mg/dL) has doubled and
the prevalence of elevated TG (greater than or equal to 150 mg/dL) has
increased five-fold.[5] Elevated TG (>150 mg/dL) is also common, affecting
about 50 percent of adults with prior CVD.[6]
Atherogenic dyslipidemia contributes to the increased risk of
macrovascular events such as myocardial infarction and stroke, and may be
implicated in microvascular complications such as diabetic eye, kidney and
lower limb disease.[7]
- Among patients achieving LDL-C <70 mg/dL with a statin, CVD risk is
almost 60 percent greater for patients with TG >200 mg/dL[8]
- In patients achieving LDL-C <70 mg/dL with a statin, CV risk was higher
in patients with a low HDL-C (HDL-C <37 mg/dL vs. those with a
HDL-C >55 mg/dL)[9]
The mission of R3i
To reduce the significant residual risk of macrovascular events and
microvascular complications which persists in most patients despite current
standards of care including achievement of low density lipoprotein goal and
intensive control of blood pressure and blood glucose.
R3i board of trustees
Professor Jean-Charles Fruchart, President Institut Pasteur de
Lille Universite, Lille2,
Lille, France
Professor Frank Sacks, Vice-President Harvard School of Public
Health and Harvard Medical
School, Boston, USA
Professor Michel P. Hermans, Cliniques Universitaires
General Secretary Saint-Luc, Brussels, Belgium
References:
---------------------------------
[1] Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, et
al. The Residual Risk Reduction Initiative: a call to action to reduce
residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102
(Suppl):1K-34K.
[2] Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, et
al. The Residual Risk Reduction Initiative: a call to action to reduce
residual vascular risk in patients with dyslipidemia. Diab Vasc Dis Res.
2008; 5:319-35.
[3] Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et
al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety
of cholesterol-lowering treatment: prospective meta-analysis of data from
90,056 participants in 14 randomised trials of statins. Lancet.
2005;366:1267-78
[4] Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O.
Multifactorial intervention and cardiovascular disease in patients with type
2 diabetes. N Engl J Med. 2003;348:383-393
[5] Alsheikh-Ali AA, Lin JL, Abourjaily P, Ahearn D, Kuvin JT, Karas RH.
Prevalence of low highdensity lipoprotein cholesterol in patients with
documented coronary heart disease or riskequivalent and controlled
low-density lipoprotein cholesterol. Am J Cardiol. 2007;100:1499-1501
[6] Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS.
Association of the metabolic syndrome with history of myocardial infarction
and stroke in the Third National Health and Nutrition Examination Survey.
Circulation. 2004;109:42-46
[7] Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen
MR, Groop L. Cardiovascular morbidity and mortality associated with the
metabolic syndrome. Diabetes Care. 2001;24:683-689
[8] Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E. Impact of
triglyceride levels beyond low-density lipoprotein cholesterol after acute
coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol.
2008;51:724-730
[9] Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM,
Kastelein JJ, Bittner V, Fruchart JC. HDL cholesterol, very low levels of LDL
cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301-1310
SOURCE Residual Risk Reduction Initiative Foundation