Metabola Syndromet

2006

Björn Carlsson

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 factors

Alcohol intake

Exercise

Psychosocial stress

Current 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

Obesity in the US 1985

Obesity in the US 1990

Obesity in the US 1993

Obesity in the US 1998

Obesity in the US 2001

Today 30% of adults in the US are obese and >65% are overweight

From Mokdad et al, JAMA 2003

Obesity is a major driver of obesity and diabetes

Diabetes/obesity

Pandemic of obesity and type 2 diabetes mellitus continues

Foreseen effects in the USA– Life time risk of developing diabetes for

individuals born in 2000• Men 32.8%• Women 38.5%

– Life expectancy reduction if diabetes diagnosed at age <40

• Men: loss of 11.6 life years • Women: 14.3 life years

Ref. JAMA. 2003;209:1884-90.

A cluster of “non-typical” CV risk factors

Increases lifetime risk of developing type II diabetes and cardiovascular diaseseControversial disease etiology

– Insulin resistance– Visceral obesity

Metabolic Syndrome 2005

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

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

theheart.org

Despite therapeutic advances, cardiovascular disease remains the

leading cause of death (USA)

0

100

200

300

400

500

Heartdisease and

stroke

Cancer Accidents Chroniclower resp.

disease

Diabetes0

510

15

20

25

30

35

Nu

mb

er o

f d

eath

s (t

ho

usa

nd

s)

Male Female

% of all deaths(right axis)

No. of deaths(left axis)

% A

ll death

s (male +

female)

National Center for Health Statistics 2004Data for 2002

Multiple cardiovascular risk factors drive adverse clinical outcomes

Abdominalobesity

DyslipidaemiaHypertension

Glucose intoleranceInsulin resistance

Increased Cardiometabolic Risk

Metabolic Syndrome

Substantial residual cardiovascular risk in statin-treated patients

Placebo Statin

Year of follow-up

% P

atie

nts

0 1 2 3 4 5 6

10

20

30

0

Risk reduction=24%(p<0.0001)

The MRC/BHF Heart Protection Study

Heart Protection Study Collaborative Group (2002)

19.8% of statin-treatedpatients had a majorCV event by 5 years

Unmet clinical needs to address in the next decade

CARDIOVASCULAR DISEASE

Classical Risk Factors Novel Risk Factors

Major Unmet Clinical Need

Metabolic syndromeMetabolic syndrome

AbdominalObesity

HDL-C

TG

TNF IL-6

PAI-1

Glu

Insulin

T2DM Smoking LDL-C BP

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)

High waist circumference

Plus 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

Abdominal obesity and waist circumference thresholds

New IDF criteria:

NCEP 2002; International Diabetes Federation (2005)

Current NCEP ATP-III criteria

>102 cm (>40 in) in men, >88 cm (>35 in) in women

Men Women

Europid >94 cm (37.0 in) >80 cm (31.5 in)

South Asian >90 cm (35.4 in) >80 cm (31.5 in)

Chinese >90 cm (35.4 in) >80 cm (31.5 in)

Japanese >85 cm (33.5 in) >90 cm (35.4 in)

High waist circumference is associated with multiple cardio vascular risk factors

30

20

10

0Low

HDL-Ca

HighTGb

HighFPGc

HighBPd

>2 riskfactorse

Pre

vale

nce

of

hig

h w

aist

circ

um

fere

nce

asso

ciat

ed w

ith

(%

)

a<40 mg/dL (men) or <50 mg/dL (women); b>150 mg/dL; c>110 mg/dL; d>130/85 mmHg; eNCEP/ATP III metabolic syndrome

US population age >20 years

NHANES 1999–2000 cohort; data on file

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

USa 36.9 55.1 46.0

Spainb 30.5 37.8 34.7

Italyc 24.0 37.0 31.5

UKd 29.0 26.0 27.5

Francee – – 26.3

Netherlandsf 14.8 21.1 18.2

Germanyg 20.0 20.5 20.3

Abdominal obesity has reached epidemic proportions worldwide

aFord et al 2003; bAlvarez-Leon et al 2003; cOECI 2004; dRuston et al 2004; eObepi 2003; fVisscher & Seidell 2004; gLiese et al 2001

Men (%) Women (%) Total (%)

High waist circumference: >102 cm (>40 in) in men or >88 cm (>35 in) in womenexcept in Germany (>103 cm [41 in] and >92 cm [36 in], respectively)

Growing prevalence of abdominal obesity

+ 18%55.1%46.7%Women

+ 28%36.9%29.5%Men

Relative change

NHANES (1999–2000)

NHANES III(1988–1994)

Ford et al 2003

US National Health andNutrition Examination Survey (NHANES)

Abdominal obesity defined as waist circumference: >102 cm (>40 in)in men or >88 cm (>35 in) in women

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 ri

sk

Waist circumference (cm)

Carey et al 1997

Metabolic syndrome has a negative impact on CV health and mortality

0

5

10

15

20

25

CHD MI Stroke

Pre

vale

nce

(%

)

No metabolic syndromeMetabolic syndrome

*p<0.001

Isomaa et al 2001

*

0

5

10

15

20

25

All-cause mortality

Cardiovascular mortality

Mo

rtal

ity

rate

(%

)

*

*

*

*

*p<0.001

Abdominal obesity: a major underlying cause of acute myocardial infarction

Yusuf et al 2004

PA

R (

%)a

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

Abdominal obesity predicts the risk of CVD beyond BMI

Cardiometabolic risk factors in the InterHeart Study

0

20

40

60

18

HTN

10

Diabetes

20

Abdom.Obesity

49

Abn Lipids

Abdominal obesity and increased risk of cardiovascular events

Dagenais et al 2005

Ad

just

ed r

elat

ive

risk

1 1 1

1.17 1.16 1.14

1.29 1.27

1.35

0.8

1

1.2

1.4

CVD death MI All-cause deaths

Tertile 1Tertile 2Tertile 3

Men Women<95

95–103>103

<8787–98>98

Waistcirc. (cm):

Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-C, total-C

The HOPE Study

Abdominal obesity predicts adverse outcomes such as sudden death

1

0

2

3

4

1 2 3 4 5

1

0

2

3

4

1 2 3 4 5

Ag

e-ad

just

edre

lati

ve r

isk

Ag

e-ad

just

edre

lati

ve r

isk

Quintile of sagittalabdominal diameter (SAD)

Quintile of BMI

p for trend=0.0003

The Paris Prospective Study

Empana et al 2004

Quintile 1 2 3 4 5SAD (cm) 12–19 20–21 22–23 24 25–35BMI (kg/m2) <23.2 23.2–24.9 25.0–26.6 26.7–28.4 28.5–47.7

SAD is a better predictor of

risk of sudden death than BMI

Abdominal obesity andincreased risk of CHD

Waist circumference was independently associated with increased age-adjusted risk of CHD, even after adjusting for

BMI and other CV risk factors

0.0

0.5

1.0

1.5

2.0

2.5

3.0

<69.8 69.8-<74.2 74.2-<79.2 79.2-<86.3 86.3-<139.7

1.27

2.06 2.31

2.44p for trend = 0.007

Rel

ativ

e ri

sk

Rexrode et al 1998

Quintiles of waist circumference (cm)

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

Liver

Pancreas

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 Inflammation

Pro-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

Systemic inflammation and adverse cardiovascular outcomes

0

1

2

3

4

5

Rel

ativ

e ri

sk o

f M

I

Cholesterol/HDL cholesterol ratiohs-C

RP

1.0 1.2

2.8

1.1

1.3 2.5

3.4

4.4

Low LowMedium

High

Medium High

Physicians' Health Study: 9-year follow-up

Ridker et al 1998

2.8

Intra-abdominal adiposity and dyslipidaemia

Pouliot et al 1992

310

248

186

124

62

0

60

45

30m

g/d

L

mg

/dL

Triglycerides

Lean

HDL-cholesterol

Visceral fat(obese subjects)

Low High Lean

Visceral fat(obese subjects)

Low High

Intra-abdominal adiposity and glucose metabolism

Pouliot et al 1992

IAA: intra-abdominal adipositySignificantly different from 1non-obese, 2obese with low intra-abdominal adiposity levels

Time (min) Time (min)

1

1

11

11,2

11

1mm

ol/

L

0

3

6

9

12

15

0 60 120 180

1,2

0

400

800

1200

1,2

1,2

1,2 1,2

1,21,2

1,2

1,2

1

Are

a

1,2

Are

a

0 60 120 180p

mo

l/L

InsulinGlucose

Non-obese Obese low IAA Obese high IAA

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

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

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

Can we change our life-style?

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Thank you for your attention!