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. 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)

7
Necessary Criteria to Make Diagnosis

• WHO
• Impaired G handling 2 other criteria.
• Also requires microalbuminuria - Albumen/
  creatinine ratio gt30 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 (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
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 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
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
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
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) lt23.2 23.224.9 25.026.6 26.7
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
lt71
7175.9
7681
81.186
86.191
91.196.3
gt96.3
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
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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

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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
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

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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
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
plt0.001
0.8
plt0.001
0.6
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
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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

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

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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

38
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)

39
Multiple Risk Factor Management

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

40
Glucose Abnormalities

• IDF
• FPG gt100 mg/dL (5.6 mmol. L) or previously
  diagnosed type 2 diabetes
• WHO
• Presence of diabetes, IGT, IFG, insulin
  resistance
• ATP III
• FBS gt110 mg/dL, lt126 mg/dL (6.1-7.1 mmol/L )
• (ADA FBS gt100 mg/dL 5.6 mmol/L )

41
Hypertension

• IDF
• BP gt130/85 or on Rx for previously diagnosed
  hypertension
• WHO
• BP gt140/90
• NCEP ATP III
• BP gt130/80

42
Dyslipidemia

• IDF
• Triglycerides - gt150mg/dL (1.7 mmol /L)
• HDL - lt40 mg/dL (men), lt50 mg/dL (women)
• WHO
• Triglycerides - gt150 mg/dL (1.7 mmol/L)
• HDL - lt35 mg/dL (men), gt39 mg/dL) women
• ATP III
• Same as IDF

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Adipocytokines and Insulin Resistance
Adipokines and Metabolic Syndrome
44
INSULIN MODULATION OF ENDOTHELIAL ACTIVITIES
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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

47
Screening/Public Health Approach

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

48
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.

49
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.

50
Diabetes Control - How Important?

• 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 lt110,
• postmeal lt180.
• HbA1c lt7

51
Overcome Insulin Resistance/ Diabetes

• Insulin Sensitizers
• Biguanides - metformin
• PPAR a, ? d agonists Glitazones, Gltazars
• Rosiglitazon,
  Pioglitazon
• Can be used in combination
• Insulin Secretagogues
• Sulfonylurea - glipizide, glyburide,
  glimeparide, glibenclamide
• Meglitinides - repaglanide, netiglamide

52
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

53
BP Control - How Important?

• 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.lt130/80

54
Lipid Control - How Important?

• Multiple major studies show 24 - 37 reductions
  in cardiovascular disease risk with use of
  statins and fibrates in the control of
  hyperlipidemia.
• Goals LDL lt100 mg/dL (lt3.0 mmol /l)
• (high risk lt70 mg/dL- lt2.6
  mmol/L)
• TG lt150 mg (lt1.7 mmol /l)
• HDL gt40 mg (gt1.1 mmol /l)

55
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

56
Antihypertensive Medications

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

57
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 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 its
  individual components.
• ADA EASD

58
A Critical Look at the Metabolic Syndrome

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

59
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)

61
Multivariate logistic regression analysis of
factors associated with Metabolic Syndrome
according to (ATP III criteria)

• Odds ratio 95 CI p-Value
• Age 1.07 1.051.09 lt0.001
• Female gender 1.86 1.302.67 0.001
• Body Mass Index 1.05 1.021.07 lt0.001
• Fam his of DM 1.66 1.122.44 0.011
• Smoking 3.27 1.636.55 0.001

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Prevalence of MeS in different Countries
Crude rates Mussallam et
al. Int J Food Safety and PH 2008
63
Prevalence of MeS in different Countries
Crude rates Mussallam et
al. Int J Food Safety and PH 2008
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Thank You
68
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

69
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)

70
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

71
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
73
Developing A New Definition of the Metabolic
Syndrome 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

74
International Diabetes Federation (IDF) Consensus
Definition 2005

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

75
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
77
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.

80
International Diabetes Federation (IDF) Consensus
Definition 2005

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

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International Diabetes Federation (IDF) Consensus
Definition 2005
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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.

84
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

85
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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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.