Cardiometabolic Syndrome

1

• Cardiometabolic Syndrome
• 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

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Cardiometabolic Syndrome IIAims

• Abdominal obesity prevalence
• Targeting Cardiometabolic Risk factors
• Multiple Risk Factor management
• A Critical Look at the Metabolic Syndrome

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Clustering of Components

• Hypertension BP. gt 140/90
• Dyslipidemia TG gt 150 mg/ dL ( 1.7 mmol/L )
• HDL- C lt 35 mg/ dL
  (0.9 mmol/L)
• Obesity (central) BMI gt 30 kg/M2
• Waist girth gt 94 cm
  (37 inch)
• Waist/Hip ratio gt 0.9
  
• Impaired Glucose Handling IR , IGT or DM
• FPG gt 110 mg/dL
  (6.1mmol/L)
• 2hr.PG gt200
  mg/dL(11.1mmol/L)
  
• Microalbuninuria (WHO)

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Global cardiometabolic risk
Gelfand EV et al, 2006 Vasudevan AR et al, 2005
working definition
5
International Diabetes Federation (IDF) Consensus
Definition 2005

• The new IDF definition focusses on abdominal
  obesity rather than insulin resistance

6
Why a New Definition of the MeS IDF Objectives

• Needs
• To identify individuals at high risk of
  developing cardiovascular disease (and diabetes)
• To be useful for clinicians
• To be useful for international comparisons

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Central Obesity

• IDF
• Central obesity - waist circumference gt94 cm for
  Europid men, gt80 Europid women with ethnicity
  specific values for other groups
• WHO
• Waist-hip ratio gt0.9 - men or gt0.85 - women
• ATP III
• Waist circumference gt40 in. - men,
• gt 35 in. -
  women

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Fat Topography In Type 2 Diabetic Subjects
Intramuscular
Subcutaneous
Intrahepatic
Intra- abdominal
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Abdominal obesity and increased risk of
cardiovascular events
The HOPE study
Men
Women
Tertile 1
lt95
lt87
Waistcircumference (cm)
Tertile 2
95103
8798
Tertile 3
gt103
gt98
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
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Abdominal obesity increases the risk of
developing type 2 diabetes
24
20
16
12
Relative risk
8
4
0
lt71
7175.9
7681
81.186
86.191
91.196.3
gt96.3
Waist circumference (cm)
Carey VJ et al, 1997
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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
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Diabetes in the new millenniumInterdisciplinary
problem

• Diabetes

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Diabetes in the new millenniumInterdisciplinary
problem

• OBESITY

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Diabetes in the new millenniumInterdisciplinary
problem

• DIAB
• ESITY

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• Targeting
• Cardiometabolic Risk

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Central obesity a driving force for
cardiovascular disease diabetes
Balzac by Rodin
Front
Back
17
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
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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
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• Waist Circumference

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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
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Insulin Resistance Associated Conditions
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Targeting Cardiometaboilc Risk Defining
cardiometabolic Risk

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

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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

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Linked Metabolic Abnormalities

• Impaired glucose handling/ insulin resistance
• Atherogenic dyslipidemia
• Endothelial dysfunction
• Prothrombotic state
• Hemodynamic changes
• Proinflammatory state
• Excess ovarian testosterone production
• Sleep-disordered breathing

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Resulting Clinical Conditions

• Type 2 diabetes
• Essential hypertension
• Polycystic ovary syndrome (PCOS)
• Nonalcoholic fatty liver disease
• Sleep apnea
• Cardiovascular Disease (MI, PVD, Stroke)
• Cancer (Breast, Prostate, Colorectal, Liver)

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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
• Genetic?

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Multiple Risk Factor Management

• Obesity
• Glucose Intolerance
• Insulin Resistance
• Lipid Disorders
• Hypertension
• Goals Minimize Risk of Type 2 Diabetes and
  Cardiovascular Disease

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Glucose Abnormalities

• IDF
• FPG gt100 mg/dL (5.6 mmol. L) or previously
  diagnosed type 2 diabetes
• (ADA FBS gt100 mg/dL 5.6 mmol/L )

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Hypertension

• IDF
• BP gt130/85 or on Rx for previously diagnosed
  hypertension

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Dyslipidemia

• IDF
• Triglycerides - gt150mg/dL (1.7 mmol /L)
• HDL - lt40 mg/dL (men), lt50 mg/dL (women)

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Insulin Resistance

• Hyperinsulinemic individuals are at risk for
  developing Diabetes, Dyslipidemia, Hypertension
  ultimately Cardiovascular disease
• Patients with Metabolic Syndrome are 3.5 times as
  likely to die from Cardiovascular disease
  compared to normal people

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Public Health Approach
33
Screening/Public Health Approach

• Public Education
• Screening for at risk individuals
• Blood Sugar/ HbA1c
• Lipids
• Blood pressure
• Tobacco use
• Body habitus
• Family history

34
Life-Style Modification Is it Important?

• Exercise
• Improves CV fitness, weight control, sensitivity
  to insulin, reduces incidence of diabetes
• Weight loss
• Improves lipids, insulin sensitivity, BP levels,
  reduces incidence of diabetes
• Goals
• Brisk walking - 30 min./day
• 10 reduction in body wt.

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Smoking Cessation / Avoidance

• A risk factor for development in children and
  adults
• Both passive and active exposure harmful
• A major risk factor for
• insulin resistance and metabolic syndrome
• macrovascular disease (PVD, MI, Stroke)
• microvascular complications of diabetes
• pulmonary disease, etc.

36
Diabetes Control - How Important?

• Goals
• FBS - premeal lt110,
• postmeal lt180.
• HbA1c lt7
• For every 1 rise in Hb A1c there is an 18 rise
  in risk of cardiovascular events a 28 increase
  in peripheral arterial disease
• Evidence is accumulating to show that tight blood
  sugar control in both Type 1 and Type 2 diabetes
  reduces risk of CVD

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Lifestyle modification

• If a 1 reduction in HbA1c is achieved, you could
  expect a reduction in risk of
• 21 for any diabetes-related endpoint
• 37 for microvascular complications
• 14 for myocardial infarction

• Diet
• Exercise
• Weight loss
• Smoking cessation

However, compliance is poor and most patients
will require oral pharmacotherapy within a few
years of diagnosis
Stratton IM et al. BMJ 2000 321 405412.
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Overcome Insulin Resistance/ Diabetes

• Insulin Sensitizers
• Biguanides metformin
• Glitazones, Gltazars
• Can be used in combination
• Insulin Secretagogues
• Sulfonylurea - glipizide, glyburide,
  glimeparide, glibenclamide
• Meglitinides - repaglanide, netiglamide

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Insulin

• Insulin Analogues
• Lyspro /Aspart /glulysine used with meals
• Glargine Livemer as basal insulin
• Continuous Subcutaneous Insulin Infusion (CSII)
• NPH/Regular, NPH/logs - Mixed or in fixed
  combinations (70/30, 75/25, 50/50)
• Insulin combined with oral agents

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BP Control - How Important?

• Goal BP.lt130/80
• MRFIT and Framingham Heart Studies
• Conclusively proved the increased risk of CVD
  with long-term sustained hypertension
• Demonstrated a 10 year risk of cardiovascular
  disease in treated patients vs non-treated
  patients to be 0.40.
• 40 reduction in stroke with control of HTN
• Precedes literature on Metabolic Syndrome

41
Lipid Control - How Important?

• Goals HDL gt40 mg (gt1.1 mmol /l)
• LDL lt100 mg/dL (lt3.0 mmol /l)
• TG lt150 mg (lt1.7 mmol /l)
• Multiple major studies show 24 - 37 reductions
  in cardiovascular disease risk with use of
  statins and fibrates in the control of
  hyperlipidemia.

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Substantial residual cardiovascular risk in
statin-treated patients
The MRC/BHF Heart Protection Study
30
Placebo Statin
20
Risk reduction24 (plt0.0001)
19.8 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
43
Medications

• Hypertension
• ACE inhibitors, ARBs
• Others - thiazides, calcium channel blockers,
  beta blockers, alpha blockers
• Central acting Alfa agonist Moxolidin
• Dylipidemia
• Statins, Fibrates, Niacin
• Platelet inhibitors
• ASA, clopidogrel

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Antihypertensive Medications

• Target BP lt130/80
• Angiotensin -converting Enzyme Inhibitors (ACEI)
• Angiotensin II Receptor (ARB) Blockers
• Combination with Thiazides, Calcium Channel
  Blockers, Cardioselective Beta Blockers

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Individual metabolic abnormalities among Qatari
population according to gender (Musallam et al
08)

• Men (n 405) Women (n412)
• Variable n() n() p-Value
• ATP III
• Abdominal obesity 227(56.0) 308(74.8) lt0.001
• Hypertension 143(35.3) 156(37.9) 0.448
• Diabetes 77(19.0) 107(26.0) 0.017
• Hypertriglyceridemia 113(27.9) 83(20.1) 0.009
• Low HDL 95(23.5) 121(29.4) 0.055

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Individual metabolic abnormalities among Qatari
population according to gender
No of components of ATP III

• Men (n 405) Women (n412)
• Variable n() n() p-Value
• None 88(21.7) 74(18.0)
• One 103(25.4) 100(24.3) 0.033
• Two 125(30.9) 111(26.9)
• Three or more 89(22.0) 127(30.8)

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Prevalence of MeS in different Countries
Prevalence () Sample Year Country
23 542 2003 Arab Americans
21 1419 2001 Oman
36 1121 2002 Jordan
20.8 2250 2004 Saudi Arabia
17 1998 Palestine
27.6 817 2007 Qatar
33.4 1637 2004 Turkey
33.7 10368 ? Iran
Crude rates Mussallam et
al. Int J Food Safety and PH 2008
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A Critical Look at the Metabolic Syndrome

• Is it a Syndrome?
• too much clinically important information is
  missing to warrant its designations as a
  syndrome.
• Unclear pathogenesis, Insulin resistance is not a
  consistent finding in some definitions.
• CVD risks has not shown to be greater than the
  sum of its individual components.
• ADA

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A Critical Look at the Metabolic Syndrome

• Research
• Until much needed research is completed,
  clinicians should evaluate and treat all CVD risk
  factors without regard to whether a patient meets
  the criteria for diagnosis of the metabolic
  syndrome.

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A Critical Look at the Metabolic Syndrome

• Lifestyle
• The advice remains to treat individual risk
  factors when present to prescribe therapeutic
  lifestyle changes weight management for obese
  patients with multiple risk factors.

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Insulin Resistance Associated Conditions
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Thank You
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Determinants and dynamics of the CVD Epidemic in
the developing Countries

• Data from South Asian Immigrant studies
• Excess, early, and extensive CHD in persons of
  South Asian origin
• The excess mortality has not been fully explained
  by the major conventional risk factors.
• Diabetes mellitus and impaired glucose tolerance
  highly prevalent. (Reddy KS, circ 1998).
• Central obesity, ?triglycerides, ?HDL with or
  without glucose intolerance, characterize a
  phenotype.
• genetic factors predispose to ?lipoprotein(a)
  levels, the central obesity/glucose
  intolerance/dyslipidemia complex collectively
  labeled as the metabolic syndrome

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Determinants and dynamics of the CVD epidemic in
the developing countries

• Other Possible factors
• Relationship between early life characteristics
  and susceptibility to NCD in adult hood (
  Barkers hypothesis) (Baker DJP,BMJ,1993)
• Low birth weight associated with increased CVD
• Poor infant growth and CVD relation
• Geneticenvironment interactions
• (Enas EA, Clin. Cardiol. 1995 18 1315)
• Amplification of expression of risk to some
  environmental changes esp. South Asian
  population)
• Thrifty gene (e.g. in South Asians)

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CVD epidemic in developing developed countries.
Are they same?

• Urban populations have higher levels of CVD risk
  factors related to diet and physical activity
  (overweight, hypertension, dyslipidaemia and
  diabetes)
• Tobacco consumption is more widely prevalent in
  rural population
• The social gradient will reverse as the epidemics
  mature.
• The poor will become progressively vulnerable to
  the ravages of these diseases and will have
  little access to the expensive and
  technology-curative care.
• The scarce societal resources to the treatment of
  these disorders dangerously depletes the
  resources available for the unfinished agenda
  of infectious and nutritional disorders that
  almost exclusively afflict the poor

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Burden of CVD in Pakistan

• Coronary heart disease
• Mortality statistics
• Specific mortality data ideal for making
  comparisons with other countries are not
  available
• Inadequate and inappropriate death certification,
  and multiple concurrent causes of death

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Central obesity a driving force for
cardiovascular disease diabetes
Balzac by Rodin
Front
Back
62
Why people physically inactive?

• Lack of awareness regarding the of physical
  activity for health fitness and prevention of
  diseases
• Social values and traditions regarding physical
  exercise (women, restriction).
• Non-availability public places suitable for
  physical activity (walking and cycling path,
  gymnasium).
• Modernization of life that reduce physical
  activity (sedentary life, TV, Computers, tel,
  cars).

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Insulin Resistance Associated Conditions
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Prevalence of the Metabolic Syndrome Among US
Adults NHANES 1988-1994
Age (years)
Ford E et al. JAMA. 2002(287)356.
1999-2002 Prevalence by IDF vs. NCEP Definitions
(Ford ES, Diabetes Care 2005 28 2745-9)
(unadjusted, age 20) NCEP 33.7 in men and
35.4 in women IDF 39.9 in men and 38.1
in women
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Prevention of CVD

• There is an urgent need to establish appropriate
  research studies, increase awareness of the CVD
  burden, and develop preventive strategies.
• Prevention and treatment strategies that have
  been proven to be effective in developed
  countries should be adapted for developing
  countries.
• Prevention is the best option as an approach to
  reduce CVD burden.
• Do we know enough to prevent this CVD Epidemic in
  the first place.

67
International Diabetes Federation (IDF) Consensus
Definition 2005

• The new IDF definition focusses on abdominal
  obesity rather than insulin resistance

68
International Diabetes Federation (IDF) Consensus
Definition 2005
Central Obesity Central Obesity
Waist circumference ethnicity specific for Europids Male gt 94 cm Female gt 80 cm Waist circumference ethnicity specific for Europids Male gt 94 cm Female gt 80 cm
plus any two of the following plus any two of the following
Raised triglycerides gt 150 mg/dL (1.7 mmol/L) or specific treatment for this lipid abnormality
Reduced HDL cholesterol lt 40 mg/dL (1.03 mmol/L) in males lt 50 mg/dL (1.29 mmol/L) in females or specific treatment for this lipid abnormality
Raised blood pressure Systolic gt 130 mmHg or Diastolic gt 85 mmHg or Treatment of previously diagnosed hypertension
Raised fasting plasma glucose Fasting plasma glucose gt 100 mg/dL (5.6 mmol/L) or Previously diagnosed type 2 diabetes If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly recommended but is not necessary to define presence of the syndrome.
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Treatment of Metabolic Syndrome 2005
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Recommendations for treatment

• Primary management for the Metabolic Syndrome
  is healthy lifestyle promotion. This includes
• moderate calorie restriction (to achieve a 5-10
  loss of body weight in the first year)
• moderate increases in physical activity
• change dietary composition to reduce saturated
  fat and total intake, increase fibre and, if
  appropriate, reduce salt intake.

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Management of the Metabolic Syndrome

• Appropriate aggressive therapy is essentialfor
  reducing patient risk of cardiovascular disease
• Lifestyle measures should be the first action
• Pharmacotherapy should have beneficial effects on
• Glucose intolerance/diabetes
• Obesity
• Hypertension
• Dyslipidaemia
• Ideally, treatment should address all of the
  components of the syndrome and not the individual
  components

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Summary new IDF definition for the Metabolic
Syndrome

• The new IDF definition addresses both
  clinical and research needs
• provides a simple entry point for primary care
  physicians to diagnose the Metabolic Syndrome
• providing an accessible, diagnostic tool suitable
  for worldwide use, taking into account ethnic
  differences
• establishing a comprehensive platinum standard
  list of additional criteria that should be
  included in epidemiological studies and other
  research into the Metabolic Syndrome

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