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
Agenda
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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
Metabolic Syndrome (History)
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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
Metabolic Syndrome History (cont.)
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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, InsulinResistance Syndrome - feels insulin
resistance is the common denominator for
Metabolic Syndrome
Literature now extensive
Other Names Used:
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Syndrome X
Cardiometabolic Syndrome
Cardiovascular Dysmetabolic Syndrome
Insulin-Resistance Syndrome
Metabolic Syndrome
Beer Belly Syndrome
Reaven’s Syndrome
etc.
Clustering of Components:
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Hypertension: BP. > 140/90
Dyslipidemia: TG > 150 mg/ dL ( 1.7 mmol/L )
HDL- C < 35 mg/ dL (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)
Necessary Criteria to Make Diagnosis
• WHO:
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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
What is cardiometabolic risk?*
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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
* working definition
MI: myocardial infarction; LDL: low-density lipoprotein;
HDL: high-density lipoprotein
Global cardiometabolic risk*
* working definition
Gelfand EV et al, 2006; Vasudevan AR et al, 2005
Despite therapeutic advances, CV disease
remains the leading cause of death (USA)
Data for 2002
No. of deaths
(left axis)
400
300
Male
Female
% of all deaths
(right axis)
200
100
0
Heart
disease and
stroke
Cancer
Accidents
Chronic
lower resp.
disease
35
30
25
20
15
10
5
0
% All deaths
(male + female)
Number of deaths
(thousands)
500
Diabetes
National Center for Health Statistics, 2004
Substantial residual cardiovascular
risk in statin-treated patients
The MRC/BHF Heart Protection Study
% patients
30
Placebo
Statin
20
Risk reduction=24%
(p<0.0001)
19.8% of statin-treated
patients had a major
cardiovascular event
by 5 years
10
0
0
1
2
3
4
5
6
Year of follow-up
Heart Protection Study Collaborative Group, 2002
Abdominal obesity has reached epidemic
proportions worldwide
Prevalence of abdominal obesity by region
•US1
•South Europe2
•South Korea3
•Australia4
•South Africa5
•North Europe2
Men (%)
Women (%)
Total (%)
36.9
55.1
46.0
33.2
43.8
38.5
21.0
42.4
32.5
26.8
34.1
30.5
9.2
42.0
27.3
22.8
25.9
24.4
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
Targeting Cardiometaboilc Risk
Defining cardiometabolic Risk
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What is Abdominal Obesity ?
Can be defined by Waist Circumference;
ATP- III
IDF
Male:
> 102 Cm. (> 42 Inch )
Male :
> 94 Cm. ( > 37 Inch )
Female :
> 88 Cm. (> 35 Inch )
Female :
> 80 Cm. ( > 31.5 Inch )
Fat Topography In Type 2
Diabetic Subjects
Intramuscular
Subcutaneous
Intrahepatic
Intraabdominal
FFA*
TNF-alpha*
Leptin*
IL-6 (CRP)*
Tissue Factor*
PAI-1*
Angiotensinogen*
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)
Cardiovascular risk factor
Increased waist circumference
Parameters
Men
Women
Elevated LDL- Cholesterol
Elevated triglycerides
≥102 cm (40 in)
≥88 cm (35 in)
> 2.6 mmol/L (> 70 mg/d )
1.7 mmol/L (150 mg/dL)
Low HDL- Cholesterol
Men
Women
<1.03 mmol/L (<40 mg/dL)
<1.30 mmol/L (<50 mg/dL)
Hypertension
BP
130/80 mm Hg
Elevated fasting glucose
6.1 mmol/L (110 mg/dL)
HDL: high-density lipoprotein; BP: blood pressure
National Cholesterol Education Panel/
Adult Treatment Panel III, 2002
Targeting Cardiometaboilc Risk
Defining cardiometabolic Risk
86%
24%
At least 1 additional CM risk factor
2 or more additional CM risk factors
Abdominal obesity and increased risk of
cardiovascular events
The HOPE study
Adjusted relative risk
Waist
circumference (cm):
1.4
Tertile 1
Men
<95
Women
<87
Tertile 2
Tertile 3
95–103
>103
87–98
>98
1.29
1
0.8
1.27
1.17
1.2
1
1.16
1
CVD death
1.35
1.14
1
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
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
>96.3
Waist circumference (cm)
Carey VJ et al, 1997
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
3.0
Relative risk
2.5
p for trend = 0.007
2.31
2.44
2.06
2.0
1.5
1.27
1.0
0.5
0.0
<69.8
69.8<74.2
74.2<79.2 79.2<86.3
86.3<139.7
Quintiles of waist circumference (cm)
CHD: coronary heart disease; BMI: body mass index
Rexrode KM et al, 1998
Diabetes in the new millennium
Interdisciplinary problem
Diabetes
Diabetes in the new millennium
Interdisciplinary problem
OBESITY
Diabetes in the new millennium
Interdisciplinary problem
DIAB
ESITY
Targeting
Cardiometabolic Risk
Linked Metabolic Abnormalities:
• Impaired glucose handling/ insulin
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resistance
Atherogenic dyslipidemia
Endothelial dysfunction
Prothrombotic state
Hemodynamic changes
Proinflammatory state
Excess ovarian testosterone production
Sleep-disordered breathing
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)
Multiple Risk Factor Management
• Obesity
• Glucose Intolerance
• Insulin Resistance
• Lipid Disorders
• Hypertension
• Goals: Minimize Risk of Type 2
Diabetes and Cardiovascular Disease
Glucose Abnormalities:
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IDF:
– FPG >100 mg/dL (5.6 mmol. L) or previously
diagnosed type 2 diabetes
WHO:
– Presence of diabetes, IGT, IFG, insulin resistance
ATP III:
– FBS >110 mg/dL, <126 mg/dL (6.1-7.1 mmol/L )
– (ADA: FBS >100 mg/dL [ 5.6 mmol/L ])
Hypertension:
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IDF:
– BP >130/85 or on Rx for previously
diagnosed hypertension
WHO:
– BP >140/90
NCEP ATP III:
– BP >130/80
Dyslipidemia:
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IDF:
– Triglycerides - >150mg/dL (1.7 mmol /L)
– HDL - <40 mg/dL (men), <50 mg/dL
(women)
WHO:
– Triglycerides - >150 mg/dL (1.7 mmol/L)
– HDL - <35 mg/dL (men), >39 mg/dL)
women
ATP III:
– Same as IDF
Screening/Public Health Approach
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Public Education
Screening for at risk individuals:
– Blood Sugar/ HbA1c
– Lipids
– Blood pressure
– Tobacco use
– Body habitus
– Family history
Life-Style Modification: Is it Important?
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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.
Smoking Cessation / Avoidance:
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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.
Diabetes Control - How Important?
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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
Goals:
FBS - premeal <110,
postmeal <180.
HbA1c <7%
Overcome Insulin Resistance/ Diabetes:
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Insulin Sensitizers:
– Biguanides - metformin
– PPAR α, γ & δ agonists – Glitazones, Gltazars
Rosiglitazon, Pioglitazon
– Can be used in combination
Insulin Secretagogues:
– Sulfonylurea - glipizide, glyburide,
glimeparide, glibenclamide
– Meglitinides - repaglanide, netiglamide
BP Control - How Important?
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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
Goal: BP.<130/80
Lipid Control - How Important?
• Multiple major studies show 24 - 37%
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reductions in cardiovascular disease risk with
use of statins and fibrates in the control of
hyperlipidemia.
Goals: LDL <100 mg/dL (<3.0 mmol /l)
(high risk <70 mg/dL- <2.6 mmol/L)
TG <150 mg% (<1.7 mmol /l)
HDL >40 mg% (>1.1 mmol /l)
Medications:
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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
A Critical Look at the Metabolic Syndrome
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Is it a Syndrome?*
“…too much clinically important information
is missing to warrant its designations as a
syndrome.”
Unclear pathogenesis, Insulin resistance
may not underlie all factors, & is not a
consistent finding in some definitions.
CVD risks associated with metabolic
syndrome has not shown to be greater than
the sum of it’s individual components.
*ADA & EASD
A Critical Look at the Metabolic Syndrome
• “Until much needed research is completed,
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clinicians should evaluate and treat all CVD
risk factors without regard to whether a
patient meets the criteria for diagnosis of
the ‘metabolic syndrome’.”
The advice remains to treat individual risk
factors when present & to prescribe
therapeutic lifestyle changes & weight
management for obese patients with
multiple risk factors.
Individual metabolic abnormalities among Qatari
population according to gender (Musallam et al 08)
Men (n = 405)
Women (n=412)
Variable n(%)
ATP III
n(%)
p-Value
Abdominal obesity
227(56.0)
308(74.8)
<0.001
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
Individual metabolic abnormalities among Qatari
population according to gender
No of components of ATP III
Men (n = 405)
Variable n(%)
n(%)
Women (n=412)
p-Value
None
88(21.7)
74(18.0) –
One
103(25.4)
100(24.3)
Two
125(30.9)
111(26.9) –
Three or more
89(22.0)
127(30.8) –
0.033
Multivariate logistic regression analysis of
factors associated with Metabolic Syndrome
according to (ATP III criteria)
Age
Female gender
Odds ratio
95% CI
p-Value
1.07 1.05–1.09
<0.001
1.86
1.30–2.67
0.001
Body Mass Index 1.05
1.02–1.07
<0.001
Fam his of DM
1.66
1.12–2.44
0.011
Smoking
3.27
1.63–6.55
0.001
Prevalence of MeS in different Countries
Country
Year
Sample
Prevalence
(%)
Arab Americans
2003
542
23
Oman
2001
1419
21
Jordan
2002
1121
36
Saudi Arabia
2004
2250
20.8
Palestine
1998
Qatar
2007
817
27.6
Turkey
2004
1637
33.4*
Iran
?
10368
33.7
* Crude rates
17*
Mussallam et al. Int J Food Safety and PH 2008
Prevalence of MeS in different Countries
Country
Year
Sample
Prevalence
(%)
USA
2005
2002
34*
Greece
2005
1419
21
South Australia
2005
4060
15.3
S. Korea
2001
40,698
6.8
China
2000
2776
10.2*
Turkey
2004
1637
33.4*
Chennai India
2003
475
41*
Qatar
2001
817
27.6
* Crude rates
Mussallam et al. Int J Food Safety and PH 2008
Determinants and dynamics of the CVD
Epidemic in the developing Countries
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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”
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 ( Barker’s
hypothesis)
(Baker DJP,BMJ,1993)
– Low birth weight associated with increased CVD
– Poor infant growth and CVD relation
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Genetic–environment interactions
(Enas EA, Clin. Cardiol. 1995; 18: 131–5)
- Amplification of expression of risk to some
environmental changes esp. South Asian population)
- Thrifty gene (e.g. in South Asians)
CVD epidemic in developing &
developed countries. Are they same?
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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
Burden of CVD in Pakistan
Coronary heart disease
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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
Central obesity: a driving force for
cardiovascular disease & diabetes
Front
Back
“Balzac” by Rodin
Developing A New Definition of
the Metabolic Syndrome: IDF
Objectives
Needs:
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To identify individuals at high risk of developing
cardiovascular disease (and diabetes)
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To be useful for clinicians
To be useful for international comparisons
International Diabetes Federation
(IDF) Consensus Definition 2005
The new IDF definition focusses on abdominal obesity
rather than insulin resistance
Why people physically inactive?
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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).
Insulin Resistance: Associated
Conditions
Prevalence (%)
Prevalence of the Metabolic Syndrome
Among US Adults NHANES 1988-1994
45
40
35
30
25
20
15
10
5
0
Men
Women
20-29
30-39
Ford E et al. JAMA. 2002(287):356.
40-49
50-59
60-69
> 70
Age (years)
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
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.
International Diabetes Federation
(IDF) Consensus Definition 2005
The new IDF definition focusses on
abdominal obesity rather than insulin
resistance
International Diabetes Federation (IDF)
Consensus Definition 2005
Central Obesity
Waist circumference
– ethnicity specific*
– for Europids: Male > 94 cm
Female > 80 cm
plus any two of the following:
Raised triglycerides
> 150 mg/dL (1.7 mmol/L)
or specific treatment for this lipid abnormality
Reduced HDL cholesterol
< 40 mg/dL (1.03 mmol/L) in males
< 50 mg/dL (1.29 mmol/L) in females
or specific treatment for this lipid abnormality
Raised blood pressure
Systolic : > 130 mmHg or
Diastolic: > 85 mmHg or
Treatment of previously diagnosed hypertension
Raised fasting plasma
glucose
Fasting plasma glucose > 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.
Treatment of Metabolic Syndrome: 2005
Stop
smoking
Oral hypoglycaemics
Insulin
Statins &
Fibrates
ACEI &/or A2 receptor
blockers
Diet,
Exercise,
Lifestyle
change
Aspirin
CB1 Receptor
Blocker
Antihypertensives
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.
Management of the Metabolic Syndrome
• Appropriate & 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
Dyslipidaemia
• Ideally, treatment should address all of the
components of the syndrome and not the
individual components
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
Lifestyle modification
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Diet
Exercise
Weight loss
Smoking
cessation
If a 1% reduction in HbA1c
is achieved, you could
expect a reduction in risk
of:
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21% for any diabetesrelated endpoint
37% for microvascular
complications
14% for myocardial
infarction
However, compliance is poor and most patients will require
oral pharmacotherapy within a few years of diagnosis
Stratton IM et al. BMJ 2000; 321: 405–412.