Patobio Metabolic Syndrome Dr Tini 213l42

METABOLIC SYNDROME

DEFINITION • Multiplex risk factor that arises from insulin resistance accompanying abnormal adipose deposition and function.

• combination of three or more of the following components must be present: large waist circumference, elevated triglycerides, low HDLcholesterol, raised blood pressure, and elevated fasting blood glucose. • It is comprised of a combination of risk factors for coronary heart disease, as well as for diabetes, fatty liver, and several cancers.

PREVALENSI • The International Diabetes Federation (IDF) estimates that ≈ 25% of the world's population has Metabolic Syndrome • 5 to 7% in young adults. • Low HDL is the most prevalent component of Metabolic Syndrome in young adults (Nolan et al., 2017)

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

Life style is a Driver of CVD Life style intervention

Risk factor modification

Physical inactivity

Excessive food intake Stress

Smoking

Obesity Hypertension

Diabetes Dyslipidaemia

Atherosclerosis

Chronic heart failure

Atherosclerosis

Arterial & venous thrombosis/ cardiac & cerebral events

Arrhythmia

Targeting cardiometabolic risk in patients with intra-abdominal adiposity and related comorbidities

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

Metabolic syndrome Classical Risk Factors

HDL-C Insulin

 LDL-C

 BP

Smoking

Glu

TNF IL-6 Abdominal Obesity

PAI-1

TG

CARDIOVASCULAR DISEASE

T2DM

Abdominal obesity: required for diagnosing the metabolic syndrome IDF criteria of the metabolic syndrome

High waist circumference  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 ‡or

specific treatment for these conditions

International Diabetes Federation (2005)

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

Abdominal obesity increases the risk of developing type 2 diabetes 24

Relative risk

20 16

12 8 4

0 <71

71–75.9

76–81

81.1–86

86.1–91 91.1–96.3

Waist circumference (cm) Carey et al 1997

>96.3

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 Abdominal obesity (High waist circumference)

Cardiovascular risk factors

Intra-abdominal adiposity

CV disease

Frayn 2002; Caballero 2003; Misra & Vikram 2003

The evolving view of adipose tissue: an endocrine organ Old View: inert storage depot Fatty acids

Fed

Current View: secretory/endocrine organ

Glucose

Multiple secretory products

Tg Tg Tg

Muscle

Fasted Liver Pancreas

Fatty acids

Glycerol

Lyon CJ et al 2003

Vasculature

Intra-abdominal adiposity promotes insulin resistance and increased CV risk  Secretion of  Hepatic FFA flux metabolically active (portal hypothesis) substances (adipokines)  Intra-abdominal adiposity  PAI-1  suppression of lipolysis by insulin

 FFA

 Insulin resistance  Dyslipidaemia

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

 Adiponectin  IL-6  TNF

Net result:  Insulin resistance  Inflammation

Adverse cardiometabolic effects of products of adipocytes ↑ Lipoprotein lipase

↑ Agiotensinogen

↑ IL-6

Inflammation

Hypertension ↑ Insulin

↑ TNFα

Adipose

tissue

↑ Adipsin (Complement D) ↓ Adiponectin

Atherosclerosis

↑ FFA ↑ Resistin ↑ Leptin ↑ Lactate

↑ Plasminogen activator inhibitor-1 (PAI-1)

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

Atherogenic dyslipidaemia

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

 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

 Small, dense LDL-C

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 b-cells Decreased insulin secretion

Pathophysiology of the metabolic syndrome leading Genetic variation to atherosclerotic CV disease 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 Physical inactivity

Life style intervention

Excessive food intake Stress

Smoking Obesity

Hypertension

Risk factor modification

Disease intervention/ secondary prevention

Diabetes Dyslipidaemia

Atherosclerosis Chronic heart failure

Atherosclerosis

Arterial & venous thrombosis/ cardiac & cerebral events

Arrhythmia

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)

Summary 

Despite 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 intraabdominal adiposity (IAA)



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

TERIMAKASIH