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
• Reaven’s Syndrome
• etc.

6. Clustering of Components:
• 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)

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
* working definition
MI: myocardial infarction; LDL: low-density lipoprotein;
HDL: high-density lipoprotein

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)
0
100
200
300
400
500
Heart
disease and
stroke
Cancer Accidents Chronic
lower resp.
disease
Diabetes
0
5
10
15
20
25
30
35
Number
of
deaths
(thousands)
Male
Female
% of all deaths
(right axis)
No. of deaths
(left axis)
%
All
deaths
(male
+
female)
National Center for Health Statistics, 2004
Data for 2002

11. Substantial residual cardiovascular
risk in statin-treated patients
Placebo
Statin
Year of follow-up
%
patients
0 1 2 3 4 5 6
10
20
30
0
Risk reduction=24%
(p<0.0001)
The MRC/BHF Heart Protection Study
Heart Protection Study Collaborative Group, 2002
19.8% of statin-treated
patients had a major
cardiovascular event
by 5 years

12. Abdominal obesity has reached epidemic
proportions worldwide
Men (%) Women (%) Total (%)
•US1 36.9 55.1 46.0
•South Europe2 33.2 43.8 38.5
•South Korea3 21.0 42.4 32.5
•Australia4 26.8 34.1 30.5
•South Africa5 9.2 42.0 27.3
•North Europe2 22.8 25.9 24.4
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;
ATP- III IDF
Male:
> 102 Cm. (> 42 Inch )
Female :
> 88 Cm. (> 35 Inch )
Male :
> 94 Cm. ( > 37 Inch )
Female :
> 80 Cm. ( > 31.5 Inch )

14. Fat Topography In Type 2
Diabetic Subjects
Intramuscular
Intrahepatic
Subcutaneous
Intra-
abdominal
FFA*
TNF-alpha*
Leptin*
IL-6 (CRP)*
Tissue Factor*
PAI-1*
Angiotensinogen*

15. Patients with abdominal obesity often present with one or more
additional cardiovascular risk factors (NCEP ATP III criteria)
Abdominal obesity is linked to multiple
cardiometabolic risk factors
National Cholesterol Education Panel/
Adult Treatment Panel III, 2002
Cardiovascular risk factor Parameters
Increased waist circumference Men ≥102 cm (40 in)
Women ≥88 cm (35 in)
Elevated LDL- Cholesterol
Elevated triglycerides
> 2.6 mmol/L (> 70 mg/d )
1.7 mmol/L (150 mg/dL)
Low HDL- Cholesterol Men <1.03 mmol/L (<40 mg/dL)
Women <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

16. Targeting Cardiometaboilc Risk
Defining cardiometabolic Risk
86% At least 1 additional CM risk factor
24% 2 or more additional CM risk factors

17. Abdominal obesity and increased risk of
cardiovascular events
Dagenais GR et al, 2005
Adjusted
relative
risk
1 1 1
1.17 1.16 1.14
1.29 1.27
1.35
0.8
1
1.2
1.4
CVD death MI All-cause deaths
Tertile 1
Tertile 2
Tertile 3
Men Women
<95
95–103
>103
<87
87–98
>98
Waist
circumference (cm):
The HOPE study
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

18. Abdominal obesity increases the risk of
developing type 2 diabetes
<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3
24
20
16
12
8
4
0
Relative
risk
Waist circumference (cm)
Carey VJ et al, 1997

19. 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
0.0
0.5
1.0
1.5
2.0
2.5
3.0
<69.8 69.8<74.2 74.2<79.2 79.2<86.3 86.3<139.7
1.27
2.06
2.31
2.44
p for trend = 0.007
Relative
risk
Quintiles of waist circumference (cm)
Rexrode KM et al, 1998
CHD: coronary heart disease; BMI: body mass index

20. Diabetes in the new millennium
Interdisciplinary problem
Diabetes

21. Diabetes in the new millennium
Interdisciplinary problem
OBESITY

22. Diabetes in the new millennium
Interdisciplinary problem
DIAB
ESITY

23. Targeting
Cardiometabolic Risk

24. 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

25. 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)

26. Multiple Risk Factor Management
• Obesity
• Glucose Intolerance
• Insulin Resistance
• Lipid Disorders
• Hypertension
• Goals: Minimize Risk of Type 2
Diabetes and Cardiovascular Disease

27. Glucose Abnormalities:
• 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 ])

28. Hypertension:
• IDF:
– BP >130/85 or on Rx for previously
diagnosed hypertension
• WHO:
– BP >140/90
• NCEP ATP III:
– BP >130/80

29. Dyslipidemia:
• 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

30. Screening/Public Health Approach
• Public Education
• Screening for at risk individuals:
– Blood Sugar/ HbA1c
– Lipids
– Blood pressure
– Tobacco use
– Body habitus
– Family history

31. 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.

32. 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.

33. 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 <110,
• postmeal <180.
• HbA1c <7%

34. Overcome Insulin Resistance/ Diabetes:
• 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

35. 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.<130/80

36. 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 <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)

37. 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

38. 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 it’s individual components.
*ADA & EASD

39. 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.

40. Individual metabolic abnormalities among Qatari
population according to gender (Musallam et al 08)
Men (n = 405) Women (n=412)
Variable n(%) n(%) p-Value
ATP III
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

41. Individual metabolic abnormalities among Qatari
population according to gender
Men (n = 405) Women (n=412)
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) –
No of components of ATP III

42. Multivariate logistic regression analysis of
factors associated with Metabolic Syndrome
according to (ATP III criteria)
Odds ratio 95% CI p-Value
Age 1.07 1.05–1.09 <0.001
Female gender 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

43. 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

44. Prevalence of MeS in different Countries
Prevalence
(%)
Sample
Year
Country
34*
2002
2005
USA
21
1419
2005
Greece
15.3
4060
2005
South Australia
6.8
40,698
2001
S. Korea
10.2*
2776
2000
China
33.4*
1637
2004
Turkey
41*
475
2003
Chennai India
27.6
817
2001
Qatar
* Crude rates Mussallam et al. Int J Food Safety and PH 2008

49. 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”

50. 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
• 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)

51. 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

52. 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

53. Central obesity: a driving force for
cardiovascular disease & diabetes
“Balzac” by Rodin
Front
Back

54. 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

55. The new IDF definition focusses on abdominal obesity
rather than insulin resistance
International Diabetes Federation
(IDF) Consensus Definition 2005

56. 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).

57. Insulin Resistance: Associated
Conditions

58. Prevalence of the Metabolic Syndrome
Among US Adults NHANES 1988-1994
Prevalence
(%)
0
5
10
15
20
25
30
35
40
45
20-29 30-39 40-49 50-59 60-69 > 70
Men
Women
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

60. 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.

61. The new IDF definition focusses on
abdominal obesity rather than insulin
resistance
International Diabetes Federation
(IDF) Consensus Definition 2005

62. 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.

63. Treatment of Metabolic Syndrome: 2005
Aspirin
Diet,
Exercise,
Lifestyle
change
Stop
smoking
CB1 Receptor
Blocker
Oral hypoglycaemics
Antihypertensives
Statins &
Fibrates
Insulin
ACEI &/or A2 receptor
blockers

64. 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.
Recommendations for treatment

65. • 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
Management of the Metabolic Syndrome

66. 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

68. Lifestyle modification
• Diet
• Exercise
• Weight loss
• Smoking
cessation
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
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.