01.09.2009 – 14:36

Residual Risk Reduction Initiative Foundation

New Insights Link Low HDL-Cholesterol and Elevated Triglycerides With Coronary Heart Disease and Microvascular Complications in Patients at Goal for LDL-Cholesterol

Barcelona (ots/PRNewswire)

• 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 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 (<45 mg/dL) and an elevated
      level of TG (>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 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 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: 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 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
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 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 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

Contact:

For further information please contact: Denis Abbonato, MS&L, Phone:
+44-20-7878-3129, Mobile: +44-7932-483-904, E-mail:
denis.abbonato@mslworldwide.com