METABOLIC SYNDROME

Apex Block III, delkurs IV HT 2006

INTER-HEART: Population-attributable risk of acute MI in the overall population

”Disease” related risk factors- Diabetes- Hypertension- Abdominal obesity- ApoB/ApoA1

Behaviour related risk factorsAlcohol intakeExercisePsychosocial stressCurrent smoking

Chronic heart failure

ArrhythmiaArterial & venousthrombosis/

cardiac & cerebral events

AtherosclerosisAtherosclerosis

HypertensionDiabetes

Dyslipidaemia

Obesity

StressSmoking

Physicalinactivity

Excessivefood intakeLife style

intervention

Risk factor modification

Life style is a Driver of CVD

Metabolic Syndrome 2005IDF Consensus

definition(a)

ATPIII: the metabolic syndrome

(b)

WHO(c)

EGIR(d)

Hyper TG waist(e)

AACC(f)

International Diabetes Federation & input from IAS/NCEP

National Cholesterol Education Program – Adult Treatment Panel III

1999 World Health Organization definition of the metabolic syndrome

European Group for the Study of Insulin Resistance (IR)

The Hypertriglyceridemic Waist in Men

American Association of Clinical Endocrinologists**

Defined as abdominal obesity (as measured by waist circumference against ethnic and gender specific cut-points) plus any two of the following:    Hypertriglyceridemia (> 150 mg/dl; 1.7mmol/l)    Low HDLc (<40 mg/dl or <1.03mmol/l for men and <50 mg/dl or 1.29 mmol/l) for women) or on treatment for low HDL    Hypertension (SBP > 130 mmHg DBP > 85 mmHg or on treatment    Hyperglycemia – Fasting Plasma Glucose > 100 mg/dl or 5.6 mmol/l or IGT or pre-existing diabetes mellitus)

Diagnosis is established when > 3 of these risk factors are present      Abdominal obesity (waist circumference) Men >102 cm (>40 in)Women >88 cm (>35 in)      Hypertriglyceridemia > 150 mg/dL      Low HDLc Men <40 mg/dLWomen <50 g/dL      Hypertension>130/>85 mm Hg      HypergylcemiaFasting Plasma Glucose >110 mg/dL

Defined as Insulin Resistance (IR)* plus any two of the following:   Obesity BMI (>30 kg/m2) and/or WHR (>0.90 in men, >0.85 in women)   Hypertriglyceridemia (>1.7 mmol/l) and/or low HDL cholesterol (<0.9 mmol/l in men, <1.0 mmol/l in women)   Hypertensive . antihypertensive treatment and/or elevated blood pressure (>140 mmHg systolic or >90 mmHg diastolic)   Microalbuminuria (urinary albumin excretion rate (AER) >30 µg/min

   IR: Fasting insulin highest 25% of populationPlus two of the following:   Abdominal obesity (waist circumference) Men >94 cm: women >80 cm    Hypertriglyceridemia >2 mmol/l   And/or low HDLc <1 mmol/l   Hypertension >140/90 mm Hg    Hyperglycaemia Fasting plasma glucose >6.1 mmol/l 

  Triglyceride >2.0 mmol/l  Waist >90 cm

   BMI >25 kg/m2   Tg >150 mg/dl   HDLcMen <40 mg/dl Women <50 mg/dl   Bp >130/85 mmHg   2 hours post glucose challenge BS >140 mg/dl   Fasting glucose 110-126 mg/dl   Others   Family history T2DM, HTN or CVD   PCO   Sedentary   Advancing Age   Ethnic group at high risk 

Targeting cardiometabolic risk in patients with

intra-abdominal adiposity and related comorbidities

Multiple cardiovascular risk factors drive adverse clinical outcomes

Abdominalobesity

DyslipidaemiaHypertension

Glucose intoleranceInsulin resistance

Increased Cardiometabolic Risk

Metabolic Syndrome

Unmet clinical needs to address in the next decade

CARDIOVASCULAR DISEASE

Classical Risk Factors Novel Risk Factors

Major Unmet Clinical Need

Metabolic syndrome

AbdominalObesity

HDL-C

TG

TNF IL-6

PAI-1

Glu

Insulin

T2DM Smoking LDL-C BP

High waist circumferencePlus any two of Triglycerides ( 1.7 mmol/L [150 mg/dL])‡

HDL cholesterol‡

– Men < 1.0 mmol/L (40 mg/dL)– Women < 1.3 mmol/L (50 mg/dL)

Blood pressure 130 / >85 mm Hg‡

FPG ( 5.6 mmol/L [100 mg/dL]), or diabetes

IDF criteria of the metabolic syndrome

Abdominal obesity: required for diagnosing the metabolic syndrome

International Diabetes Federation (2005)

‡or specific treatment for these conditions

Unmet clinical need associated with abdominal obesity

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

CV risk factors in a typical patient with abdominal obesity

Abdominal obesity increases the risk of developing type 2 diabetes

<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3

24

20

16

12

8

4

0

Rel

ativ

e ris

k

Waist circumference (cm)

Carey et al 1997

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

AbdominalObesityDyslipidemia

HypertensionGlucose IntoleranceInsulin Resistance

Increased Cardiometabolic Risk

Intra-AbdominalAdiposity

Adapted from Eckel et al 2005

Intra-abdominal adiposity: a root cause of cardiometabolic disease

Intra-abdominaladiposity

CVdisease

Cardiovascularrisk factors

Direct

Indirect

Intra-abdominal adiposity is characterised by accumulation offat around and inside abdominal organs

Frayn 2002; Caballero 2003; Misra & Vikram 2003

Abdominal obesity(High waist circumference)

Multiple secretoryproducts

LiverPancreas

Muscle

Vasculature

Current View: secretory/endocrine organOld View: inert storage depot

Fatty acids Glucose

Fatty acids Glycerol

Fed

Fasted

TgTg

Tg

The evolving view of adipose tissue:an endocrine organ

Lyon CJ et al 2003

Intra-abdominal adiposity promotes insulin resistance and increased CV risk

Hepatic FFA flux(portal hypothesis)

Secretion ofmetabolically active

substances (adipokines)

suppression of lipolysis by insulin

FFA

Insulin resistance Dyslipidaemia

PAI-1

Adiponectin

IL-6

TNF

Intra-abdominaladiposity

Net result: Insulin resistance InflammationPro-atherogenic

Heilbronn et al 2004; Coppack 2001;Skurk & Hauner 2004

Adverse cardiometabolic effects of products of adipocytes

Adiposetissue

↑ IL-6

↓ Adiponectin

↑ Leptin

↑ TNFα

↑ Adipsin(Complement D)

↑ Plasminogenactivator inhibitor-1

(PAI-1)

↑ Resistin

↑ FFA↑ Insulin

↑ Agiotensinogen

↑ Lipoprotein lipase

↑ Lactate

Inflammation

Type2 diabetes

Hypertension

Atherogenicdyslipidaemia

ThrombosisAtherosclerosis

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

Adiponectin in IAA

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

IL-6 in IAA

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

TNF in IAA

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

PAI-1 in IAA

Pro-atherogenic: atherothrombotic risk

Properties of key adipokines

IAA: intra-abdominal adiposity

Marette 2002

Suggested role of intra-abdominal adiposity and FFA in insulin resistance

FFA: free fatty acidsCETP: cholesteryl estertransfer protein

Intraabdominaladiposity

Portalcirculation

Hepaticglucoseoutput

Hepaticinsulinresistance

Systemic circulation

TG-richVLDL-C

Small,denseLDL-CLipolysis

LowHDL-C

CETP,lipolysis

Glucose utilisation

Insulin resistance

FFA

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

Intra abdominal adiposity impairs pancreatic b-cell function

Haber et al 2003; Zraika et al 2002

FFA

Long-term damageto -cellsDecreased insulinsecretion

Short-termstimulationof insulinsecretion

Intra abdominal adiposity

FFA: Free fatty acids

Splanchnic & systemiccirculation

Reilly & Rader 2003;Eckel et al 2005

Plaque rupture/thrombosis

Cardiovascular events

Atherosclerosis

Insulin resistance Tg Metabolic syndrome HDL

BP

Inflammatory markers

Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease

Adipocyte Monocyte/macrophage

Genetic variation Environmental factors

Abdominal obesity

CytokinesAdipokines

Chronic heart failure

ArrhythmiaArterial & venousthrombosis/

cardiac & cerebral events

AtherosclerosisAtherosclerosis

HypertensionDiabetes

Dyslipidaemia

Obesity

StressSmoking

Physicalinactivity

Excessivefood intake

Life style intervention

Risk factor modification

Disease intervention/ secondary prevention

A Broad Approach to Prevention and Treament of Cardiovascular Disease

Management of the metabolic syndrome

Appropriate and aggressive therapy is essential for reducing patient risk of cardiovascular disease

Lifestyle measures should be the first action

Pharmacotherapy should have beneficial effects on– Glucose intolerance / diabetes– Obesity– Hypertension– Dyslipidemia

Ideally, treatment should address all of the components of the syndrome and not the individual components

International Diabetes Federation, 1st International Congress on“Prediabetes” and Metabolic Syndrome (2005)

SummaryDespite therapeutic advances, cardiovascular disease remains the leading cause of death worldwide

Current treatments generally target individual risk factors and do not propose a comprehensive approach to the management of cardiometabolic disease

An increased risk of developing cardiometabolic disease can be attributed to abdominal obesity (as measured by waist circumference)

A major cause of cardiometabolic disorders (including dyslipidaemia, insulin resistance, type 2 diabetes, metabolic syndrome, inflammation and thrombosis) is thought to be intra-abdominal adiposity (IAA)

Waist circumference provides a simple and practical diagnosis of IAA in patients at elevated CV risk

Thank you for your attention!