Cardiometabolic Syndrome

1

• Cardiometabolic Syndrome
• Dr. Nabil Sulaiman
• HOD Family and Community Medicine, Sharjah
  University and University of Melbourne
• Dr Dhafir A. Mahmood
• Consultant Endocrinologist
• Al- Qassimi Al-Kuwait Hospital
• Sharjah

2
Agenda

• History Definition
• Clustering component of Metabolic Syndrome
• Cardiovascular disease worldwide
• Global cardiometabolic risks
• Abdominal obesity prevalence ( National
  International )
• Intra Abdominal Adiposity associated risks
• Targeting Cardiometabolic Risk factors
• Multiple Risk Factor management
• A Critical Look at the Metabolic Syndrome

3
Metabolic Syndrome (History)

• 1923 - Kylin first to describe the clustering of
  hypertension, hyperglycemia, hyperuricemia
• 1936 - Himsworth first reported Insulin
  insensitivity in diabetics
• 1965 - Yalow and Berson developed insulin assay
  and correlated insulin levels glucose lowering
  effects in resistant and non-resistant individuals

4
Metabolic Syndrome History (cont.)

• 1988 - Reaven in his Banting lecture at the ADA
  meeting coined the term Syndrome X and brought
  into focus the clustering of features of
  Metabolic Syndrome
• Reaven now prefers the name, Insulin-Resistance
  Syndrome - feels insulin resistance is the common
  denominator for Metabolic Syndrome
• Literature now extensive

5
Other Names Used

• Syndrome X
• Cardiometabolic Syndrome
• Cardiovascular Dysmetabolic Syndrome
• Insulin-Resistance Syndrome
• Metabolic Syndrome
• Beer Belly Syndrome
• Reavens Syndrome
• etc.

6
Clustering of Components

• Hypertension BP. 140/90
• Dyslipidemia TG 150 mg/ dL ( 1.7 mmol/L )
• HDL- C (0.9 mmol/L)
• Obesity (central) BMI 30 kg/M2
• Waist girth 94 cm
  (37 inch)
• Waist/Hip ratio 0.9
  
• Impaired Glucose Handling IR , IGT or DM
• FPG 110 mg/dL
  (6.1mmol/L)
• 2hr.PG 200
  mg/dL(11.1mmol/L)
  
• Microalbuninuria (WHO)

7
Necessary Criteria to Make Diagnosis

• WHO
• Impaired G handling 2 other criteria.
• Also requires microalbuminuria - Albumen/
  creatinine ratio 30 mg/gm creatinine
• IDF
• Require central obesity plus two of the other
  abnormalities
• NCEP/ATP III
• Require three or more of the five criteria

8
What is cardiometabolic risk?

• Global cardiometabolic risk represents the
  overall risk of developing type 2 diabetes and/or
  cardiovascular disease (including MI and stroke),
  which is due to a cluster of modifiable risk
  factors/markers
• These include classical risk factors such as
  smoking, high LDL, hypertension, elevated blood
  glucose and emerging risk factors closely related
  to abdominal obesity (especially intra-abdominal
  adiposity), such as insulin resistance, low HDL,
  high triglycerides and inflammatory markers
• Cardiometabolic risk is based on the concept of
  risk continuum

MI myocardial infarction LDL low-density
lipoprotein HDL high-density lipoprotein
working definition
9
Global cardiometabolic risk
Gelfand EV et al, 2006 Vasudevan AR et al, 2005
working definition
10
Despite therapeutic advances, CV disease remains
the leading cause of death (USA)
Data for 2002
No. of deaths(left axis)
Number of deaths (thousands)
All deaths (male female)
of all deaths(right axis)
National Center for Health Statistics, 2004
11
Substantial residual cardiovascular risk in
statin-treated patients
The MRC/BHF Heart Protection Study
30
Placebo Statin
20
Risk reduction24 (p19.8 of statin-treatedpatients had a
majorcardiovascular event by 5 years
patients
10
0
0
1
2
3
4
5
6
Year of follow-up
Heart Protection Study Collaborative Group, 2002
12
Abdominal obesity has reached epidemic
proportions worldwide
Prevalence of abdominal obesity by region
1. Ford ES et al, 2003 2 Haftenberger M et al,
2002 3. Kim MH et al 2004 4. Cameron AJ et al,
2003 5. Puoane T et al, 2002
13
Targeting Cardiometaboilc Risk Defining
cardiometabolic Risk

• What is Abdominal Obesity ?
• Can be defined by Waist Circumference

14
Obesity

• IDF
• Central obesity - waist circumference 94 cm for
  Europid men, 80 Europid women with ethnicity
  specific values for other groups
• WHO
• Waist-hip ratio 0.9 - men or 0.85 - women
• ATP III
• Waist circumference 40 in. - men,
• 35 in. -
  women

15
Fat Topography In Type 2 Diabetic Subjects
Intramuscular
Subcutaneous
Intrahepatic
Intra- abdominal
16
Abdominal obesity is linked to multiple
cardiometabolic risk factors
Patients with abdominal obesity often present
with one or more additional cardiovascular risk
factors (NCEP ATP III criteria)
HDL high-density lipoprotein BP blood pressure
National Cholesterol Education Panel/Adult
Treatment Panel III, 2002
17
Targeting Cardiometaboilc Risk Defining
cardiometabolic Risk

• 86 At least 1 additional CM risk factor
• 24 2 or more additional CM risk factors

18
Abdominal obesity and increased risk of
cardiovascular events
The HOPE study
Men
Women
Tertile 1
Waistcircumference (cm)
Tertile 2
95103
8798
Tertile 3
103
98
1.4
1.35
1.29
1.27
1.17
1.16
1.2
1.14
Adjusted relative risk
1
1
1
1
0.8
CVD death
MI
All-cause deaths
Adjusted for BMI, age, smoking, sex, CVD disease,
DM, HDL-cholesterol, total-C CVD cardiovascular
disease MI myocardial infarction BMI body
mass index DM diabetes mellitus HDL
high-density lipoprotein cholesterol
Dagenais GR et al, 2005
19
Abdominal obesity predicts adverse outcomes such
as sudden death
The Paris Prospective study
Quintile of SAD
Quintile 1 2 3 4 5 SAD (cm) 1219 2021 2223 24
2535 BMI (kg/m2) 28.4 28.547.7
SAD sagittal abdominal diameter BMI body mass
index
Empana JP et al, 2004
20
Abdominal obesity increases the risk of
developing type 2 diabetes
24
20
16
12
Relative risk
8
4
0
7175.9
7681
81.186
86.191
91.196.3
96.3
Waist circumference (cm)
Carey VJ et al, 1997
21
Abdominal obesity is linked to an increased risk
of coronary heart disease
Waist circumference has been shown to be
independently associated with increased
age-adjusted risk of CHD, even after adjusting
for BMI and other cardiovascular risk factors
CHD coronary heart disease BMI body mass index
Rexrode KM et al, 1998
22
Diabetes in the new millenniumInterdisciplinary
problem

• Diabetes

23
Diabetes in the new millenniumInterdisciplinary
problem

• OBESITY

24
Diabetes in the new millenniumInterdisciplinary
problem

• DIAB
• ESITY

25

• Targeting
• Cardiometabolic Risk

26
Intra-abdominal adiposity is a major contributor
to increased cardiometabolic risk
IAA high risk fat
Dyslipidaemia
Increased cardiometabolic risk
Insulin resistance
Inflammation
IAA intra-abdominal adiposity
Kershaw EE et al, 2004 Lee YH et al, 2005
Boden G et al, 2002
27
Abdominal obesity a major underlying cause of
acute myocardial infarction
Cardiometabolic risk factors in the INTERHEART
Study
60
49
Abdominal obesity predicts the risk of CVD
beyond BMI
40
PAR ()a
20
18
20
10
0
Hypertension
Diabetes
Abdominal obesity
Abnormallipids
aProportion of MI in the total population
attributable to a specific risk factor CVD
cardiovascular disease BMI body mass index
PAR population attributable risk MI
myocardial infarction
Yusuf S et al, 2004
28
Intra-abdominal adiposity and glucose metabolism
Non-obese Obese low IAA Obese
high IAA
IAA intra-abdominal adiposity significantly
different from 1non-obese, 2obese with low
intra-abdominal adiposity levels
Pouliot MC et al, 1992
29
Intra-abdominal adiposity is closely correlated
with abdominal obesity
300
r 0.80
200
IAA (cm2)
100
IAA
0
60
80
100
120
Waist circumference (cm)

• To assess IAA, the simplest measure of abdominal
  obesity is waist circumference, which is strongly
  correlated with direct measurement of IAA by CT
  scan or MRI, considered to be the gold standard

IAA intra-abdominal adiposity CT computed
tomography MRI magnetic resonance imaging
Després JP et al, 2001 Pouliot MC et al, 2004
30

• Waist Circumference

31
Intra-abdominal adiposity and dyslipidaemia
Triglycerides
HDL-cholesterol
310
60
248
186
mg/dL
mg/dL
45
124
62
30
0
Lean
Low
High
Lean
Low
High
Visceral fat(obese subjects)
Visceral fat(obese subjects)
HDL high-density lipoprotein

Pouliot MC et al, 1992
32
Properties of key adipokines
IAA intra-abdominal adiposity IL-6
interleukin-6 TNF-a tumour necrosis factor-a
PAI-1 plasminogen activator inhibitor-1
Marette A, 2002
33
Relationship between adiponectin levels and risk
of myocardial infarction
Risk of MI for highest vs lowest quintile of
adiponectin
p0.02
1.0
p0.8
p0.6
Relative risk (95 CI)
0.4
0.2
Adjusted for agedate of blooddraw smoking
Adjusted for familyhistory alcoholexercise
Adjusted for HbA1CCRP HDL-cholesterolLDL-ch
olesterol
0.0
MI myocardial infarction HbA1c haemoglobin
A1c CRP C-reactive protein HDL high-density
lipoprotein LDL low-density lipoprotein
Pischon T et al, 2004
34
Targeting Cardiometaboilc Risk Defining
cardiometabolic Risk

• Cardiovascular Disease
• Abdominal Obesity
  Glucose intolerance
• 
  Insulin Resistance
  
• Dyslipedemia
  Hypertension

35
Targeting Cardiometaboilc Risk Defining
cardiometabolic Risk

• 
  Major Unmet Clinical Need
• Classical Risk Factors
• 
  Novel Risk Factors
• 
  Cluster Risk Factors
• 
  
• LDL-C BP Smoking DM-2 Insulin
  HDL-C TNF IL-6
• 
  Abdominal Obesity
• 
  
• 
  Glucose PAI-1 TG
• Cardiovascular
  Disease

36
Targeting Cardiometaboilc Risk

• Site of Action Mechanisms
  Addresses
• Adipose tissues Adiponectin
  Dyslipidemia
• 
  Lipogeenesis Insulin resistance
• Muscle G uptake
  Insulin resistance
• Liver Lipogeenesis
  Dyslipidemia
• 
  Insulin resistance
• GI tract Satiety signals
  Body weight
• 
  Waist circumference
• Hypothalamus Food intake
  Body weight
• 
  Waist circumference