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

    BARCELONA, Sept. 1 /CNW/ - 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 Frank Sacks from Harvard Medical School, Boston,
USA and Vice-president of R3i. "While LDL-C is appropriately the 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 Gerd Assmann, member of the R3i International Steering
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 ((less than)45
        mg/dL) and an elevated level of TG ((greater than)150 mg/dL)

    The initial macrovascular findings of REALIST were also presented by
Professor Frank Sacks, Vice-President of the R3i. This case-control study
conducted in 170 patients hospitalized with CHD in Boston, USA, at goal for
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 Michel Hermans from the Cliniques Universitaires
Saint-Luc in Brussels, Belgium, were presented by Professor Paola Fioretto,
from the Department of Medical and Surgical Sciences, University of Padua,
Italy and showed that:

    -   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
    "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 Gerd Assmann from the University of
Munster, Germany.
    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
Jean-Charles Fruchart of the University of Lille, France and President of the
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:

    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 Germany.
    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
    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
Belgium, Croatia, France, Italy, Japan, Philippines, Poland, Saudi Arabia,
Spain, Thailand, Turkey and the U.S.

    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

    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 ((less than)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 ((greater than)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 (less than)70 mg/dL with a statin, CVD
        risk is almost 60 percent greater for patients with TG (greater than)
        200 mg/dL(8)

    -   In patients achieving LDL-C (less than)70 mg/dL with a statin, CV
        risk was higher in patients with a low HDL-C (HDL-C (less than)37
        mg/dL vs. those with a HDL-C (greater than)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


    (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.

    (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.

For further information:

For further information: Denis Abbonato, MS&L, Phone: +44-20-7878-3129,
Mobile: +44-7932-483-904, E-mail:

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