ATP III Clinical Identification of the

Metabolic Syndrome
Waist circumference:

Men>102 cm (>40 in)

Women>88 cm (>35 in)

Triglycerides >150 mg/dL

HDL cholesterol:
Men<40 mg/dL
Women<50 mg/dL

Blood pressure 130/ 85 mm Hg

Fasting glucose >110 mg/dL*

* New ADA guidelines suggest >100mg/dl increases risk for Metabolic Syndrome

Life style is a Driver of CVD

Physical
inactivity

Life style
intervention

Excessive
food intake
Stress

Smoking
Obesity

Risk factor
modification

Hypertension

Diabetes
Dyslipidaemia

Atherosclerosis
Chronic
heart failure

Atherosclerosis

Arterial & venous

thrombosis/
cardiac & cerebral events

Arrhythmia

No. of deaths
(left axis)
% of all deaths
(right axis)

Male
Female

35
30
25
20
15
10
5
0

Data for 2002

National Center for Health Statistics 2004

% All deaths (male + female)

Number of deaths (thousands)

Despite therapeutic advances, cardiovascular disease

remains the leading cause of death (USA)

Multiple cardiovascular risk factors

drive adverse clinical outcomes
Increased Cardiometabolic Risk

Dyslipidaemia
Hypertension

Abdominal
obesity

Metabolic Syndrome

Glucose intolerance
Insulin resistance

Unmet clinical needs to address in the next

decade
Major Unmet Clinical Need
Novel Risk Factors

Classical Risk Factors

Metabolic syndrome
HDL-C

LDL-C

BP

Smoking

Insulin
Glu

TNF IL-6

Abdominal
Obesity

PAI-1

CARDIOVASCULAR DISEASE

TG

T2DM

Unmet clinical need associated with

abdominal obesity
CV risk factors in a typical patient with abdominal obesity

Patients with abdominal

obesity (high waist
circumference) often
present with one or more
additional
CV risk factors

Metabolic syndrome has a negative impact

on CV health and mortality
No metabolic syndrome
Metabolic syndrome

25
20

25

20

*p<0.001

15

10

*
*

Mortality rate (%)

15
Prevalence (%)

*p<0.001

*
10
5
0

0
CHD
Isomaa et al 2001

MI

Stroke

All-cause
mortality

Cardiovascular
mortality

Abdominal obesity: a major underlying

cause of acute myocardial infarction
Cardiometabolic risk factors in the InterHeart Study
60

PAR (%)a

49

Abdominal obesity predicts the

risk of CVD beyond BMI

40

20

20

18
10

0
Abn Lipids
a

Abdom.
Obesity

HTN

Proportion of MI in the total population attributable to a specific risk factor

Yusuf et al 2004

Diabetes

Abdominal obesity and

increased risk of CHD
Waist circumference was independently associated with increased ageadjusted risk of CHD, even after adjusting for BMI and other CV risk
factors
3.0

Relative risk

2.5

p for trend = 0.007

2.0
1.5

2.06

2.31

2.44

1.27

1.0
0.5
0.0

<69.8

69.8-<74.2

74.2-<79.2

79.2-<86.3

Quintiles of waist circumference (cm)

Rexrode et al 1998

86.3-<139.7

Why is abdominal obesity harmful?

Abdominal obesity
is often associated with other CV risk factors
is an independent CV risk factor

Adipocytes are metabolically active endocrine

organs, not simply inert fat storage

Wajchenberg 2000

Health threat from abdominal obesity is largely due to

intra-abdominal adiposity
Increased Cardiometabolic Risk

Dyslipidemia
Hypertension

Abdominal
Obesity

Intra-Abdominal
Adiposity
Adapted from Eckel et al 2005

Glucose Intolerance
Insulin Resistance

Intra-abdominal adiposity: a root cause

of cardiometabolic disease
Intra-abdominal adiposity is characterised by accumulation of
fat around and inside abdominal organs
Cardiovascula
r
risk factors

Abdominal obesity
(High waist
circumference)

ct
e
r
i
Ind
Intraabdominal
adiposity

Direct

Frayn 2002; Caballero 2003; Misra & Vikram 2003

CV
disease

The evolving view of adipose tissue:

an endocrine organ
Old View: inert storage depot
Fatty acids

Current View: secretory/endocrine organ

Glucose

Fed
Tg
Tg

Multiple secretory
products

Tg

Fasted

Muscle

Fatty acids

Glycerol

Liver
Pancreas

Lyon CJ et al 2003

Vasculature

Intra-abdominal adiposity promotes insulin

resistance and increased CV risk
Hepatic FFA flux
(portal hypothesis)
Intra-abdominal
adiposity

suppression of
lipolysis by insulin

FFA

Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004

Secretion of
metabolically active
substances (adipokines)
PAI-1
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation

Adverse cardiometabolic effects of products of

adipocytes
Lipoprotein lipase

Agiotensinogen

IL-6

Inflammation

Hypertension
Insulin

TNF

Adipose

tissue

Atherosclerosis

Resistin
Leptin

Adipsin
(Complement D)
Adiponectin

FFA

Atherogenic
dyslipidaemia

Lactate
Plasminogen
activator inhibitor-1
(PAI-1)

Thrombosis

Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

Type
2 diabetes

Properties of key adipokines

Adiponectin
in IAA

IL-6
in IAA

TNF
in IAA

PAI-1
in IAA

Anti-atherogenic/antidiabetic:
foam cells vascular remodelling
insulin sensitivity hepatic glucose output

Pro-atherogenic/pro-diabetic:
vascular inflammation insulin signalling

Pro-atherogenic/pro-diabetic:
insulin sensitivity in adipocytes (paracrine)

Pro-atherogenic:
atherothrombotic risk

IAA: intra-abdominal adiposity

Marette 2002

Suggested role of intra-abdominal

adiposity and FFA in insulin resistance
Intra
abdominal
adiposity

Hepatic
insulin
resistance

Portal
circulation

Hepatic
glucose
output

FFA

Lipolysis

Small,
dense
LDL-C

TG-rich
VLDL-C
CETP,
lipolysis

Systemic
circulation
FFA: free fatty acids
CETP: cholesteryl ester
transfer protein

Lam et al 2003; Carr et al 2004; Eckel et al 2005

Low
HDL-C

Glucose utilisation

Insulin resistance

Intra abdominal adiposity impairs pancreatic

b-cell function
FFA
Splanchnic & systemic
circulation
Intra abdominal
adiposity

Short-term
stimulation
of insulin
secretion
FFA: Free fatty acids
Haber et al 2003; Zraika et al 2002

Long-term damage
to -cells
Decreased insulin
secretion

Pathophysiology of the metabolic syndrome leading to

atherosclerotic CV disease
Genetic variation

Environmental factors

Abdominal obesity
Adipokines

Adipocyte

Cytokines
Inflammatory markers

Insulin resistance
Tg

Metabolic syndrome

HDL

BP
Atherosclerosis

Plaque rupture/thrombosis

Reilly & Rader 2003;

Eckel et al 2005

Cardiovascular events

Monocyte/
macrophage

A Broad Approach to Prevention and Treament of

Cardiovascular Disease
Life style
intervention

Physical
inactivity

Excessive
food intake
Stress

Smoking
Obesity

Risk factor
modification

Disease
intervention/
secondary
prevention

Hypertension

Diabetes
Dyslipidaemia

Atherosclerosis
Chronic
heart failure

Atherosclerosis

Arterial & venous

thrombosis/
cardiac & cerebral events

Arrhythmia

Current Treatments

Weight reduction
TLC: Diet and Exercise
Lower BP goals
Lower LDL goals
Statins
Metformin
Aspirin therapy