metabolic syndrome

1. The metabolic syndrome
BY
Eslam Ahmed Habba
Ass.lecturer of Tropical Medicine
Tanta Faculty Of Medicine

2. 2
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

3. 3
Metabolic Syndrome History (cont.)
• 1988 Reaven 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

4. 4
Other Names Used:
• Syndrome X
• Cardiometabolic Syndrome
• Cardiovascular Dysmetabolic Syndrome
• Insulin-Resistance Syndrome
• Metabolic Syndrome
• Beer Belly Syndrome
• Reaven’s Syndrome
• etc.

5. 5
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 circumference > 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)

6. 6
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) (ATP III)
Members
Scott M. Grundy, M.D., Ph.D.
(Chair)
University of Texas Southwestern
Medical Center at Dallas
Diane Becker, Sc.D., M.P.H.
The Johns Hopkins University
Luther T. Clark, M.D.
State University of New York,
Brooklyn
Richard S. Cooper, M.D.
Loyola University Medical School
Margo A. Denke, M.D.
University of Texas Southwestern
Medical Center at Dallas
Wm. James Howard, M.D.
Washington Hospital Center
Donald B. Hunninghake, M.D.
University of Minnesota
D. Roger Illingworth, M.D.,
Ph.D.
The Oregon Health Sciences
University
Russell V. Luepker, M.D., M.S.
University of Minnesota
Patrick McBride, M.D., M.P.H.
University of Wisconsin Hospital
and Clinics
James M. McKenney,
Pharm.D.
National Clinical Research
Richard C. Pasternak, M.D.,
F.A.C.C.
Massachusetts General
Hospital
Neil J. Stone, M.D.
Northwestern University School
of Medicine
Linda Van Horn, Ph.D, R.D.
Northwestern University
Medical School
Ex-Officio Members
H. Bryan Brewer, Jr., M.D.
National Heart, Lung, and
Blood Institute
James I. Cleeman, M.D.
(Executive Director)
National Heart, Lung, and
Blood Institute
Nancy D. Ernst, Ph.D., R.D.
National Heart, Lung, and
Blood Institute
David Gordon, M.D., Ph.D.
National Heart, Lung, and
Blood Institute
Daniel Levy, M.D.
National Heart, Lung, and
Blood Institute
Basil Rifkind, M.D.
National Heart, Lung, and
Blood Institute
Jacques E. Rossouw,
M.D.
National Heart, Lung, and
Blood Institute
Peter Savage, M.D.
National Heart, Lung, and
Blood Institute
Consultants
Steven M. Haffner, M.D.
University of Texas Health
Science Center, San
Antonio
David G. Orloff, M.D.
Food and Drug
Administration
Michael A. Proschan,
Ph.D.
National Heart, Lung, and
Blood Institute
J. Sanford Schwartz, M.D.
University of Pennsylvania
Christopher T. Sempos,
Ph.D.
State University of New

7. 7
National Cholesterol Education
Program Reports
• Adult Treatment Panel I (1988)
Adult Treatment Panel II (1993)
Adult Treatment Panel III (2001)
• Recommendations for Improving Cholesterol
Measurement (1990)
Recommendations on Lipoprotein Measurement
(1995)
• Population Strategies for Blood Cholesterol Reduction
(1990)
• Blood Cholesterol Levels in Children and Adolescents
(1991)

8. 8
ATP III Clinical Identification of the
Metabolic Syndrome
3 or more of the following:
• Waist circumference:
– Men>102 cm (>40 in)
– Women>88 cm (>35 in)
• Triglycerides >150 mg/dL
• HDL cholesterol:
– Men<40 mg/dL
– Women<50 mg/dL
• Blood pressure >130/ 85 mm Hg
• Fasting glucose >110 mg/dL*
*New ADA guidelines suggest >100mg/dl increases risk for Metabolic Syndrome

9. 9
International Diabetes Federation (IDF)
Definition
• Modified ATPIII definition
– Fasting Glucose > 100mg/dl
– Adjusted waist circumference based on
ethnicity (i.e. asians with lower waist
circumference threshold than pacific
islanders)

10. 10
Ethnic specific values for waist
circumference (IDF)
• Europeans Male ≥ 94 cm Female ≥ 80 cm
• South Asians Male ≥ 90 cm Female ≥ 80 cm
• Chinese Male ≥ 90 cm Female ≥ 80 cm
• Japanese Male ≥ 85 cm Female ≥ 90 cm
• Ethnic South and Central Use South Asian
recommendations until more specific
• Americans data are available (ATPIII)
• Eastern Mediterranean and Middle East (Arab)
populations Use European data until more specific
data are available

11. 11
The New IDF Definition
Waist Circum  94 (M), 80 (F)
Triglycerides >150 mg
HDL <40 (M) < 50 (F)
Dysglycemia FPG >100 or DM
Hypertension ≥130 / 85
Rx. for any of the above conditions
2 of 5

12. 12
The Dangerous Cluster
20-25% Global
3 times likely to have MI and stroke
Five fold risk of developing T2DM
MS & T2DM drive the CV epidemic

13. 13
Global cardiometabolic risk*
Gelfand EV et al, 2006; Vasudevan AR et al, 2005
* working definition

14. 14
Etiology – not fully elucidated
 Insulin Resistance
 Acquired causes
 Overweight and central obesity
 Physical inactivity, aging,
ethnicity
 High CHO diets (>60%)
 Proinflammatory state,
hormones
 Lipodystrophic disorders
Metabolic Syndrome

15. 15
What is this Syndrome ?
 Insulin resistance – Hyperinsulinemia
 Abd. Obesity ( WC,  WC / ht ratio),  BMI
 Hyperglycemia – IFG, IGT, T2DM
 Hypertension, Endothelial Dysfunction (ED)
 Dyslipidemia ( TG,  sLDL,  HDL)
 Pro-inflammatory state ( CRP, TNF-, IL-6)
 Pro-coagulant state ( PAI-1,  Fibrinogen)
 Premature atherosclerosis, CAD

16. 16
The Awesome Two

17. 17
Each Propels the Other
Insulin
Resistance
Central
Obesity

18. 18
IR and the Double Jeopardy !!
Insulin Resistance
Obesity DiabetesMetabolic Syndrome
Cardio Vascular Disease (CVD)
2 x 4 x
Reilly MP et al –
Circulation 2003; 108: 1546-1551

19. 19
Insulin Resistance Syndrome
Insulin
Resistance
Inadequate Insulin
production
Type 2 DM
CKD, DPR,
DPN, DAN
Hyper
Insulinemia
Metabolic
Syndrome
HT, Stroke,
PCOS, NASH
ACE Position Statement on IRS Endocr Pract. 2003;9(3)
CKD:chronic kidney disease
DPR:diabetic proliferative retinopathy
DPN:Diabetic polyneuropathy
DAN:Diabetic autonomic neuropathy
CAD

20. 20
IGT, IFG
IR, Insulin
Dyslipidemia
HypertensionED, Vessel
Visceral
obesity
Pro
Inflammatory
Pro Thrombotic
Increased
CV Risk

21. 21
Insulin Resistance
Prevalence of IR in metabolic disorders –
Bruneck Study, Diabetes 1998: 47: 1643-49

22. 22

23. 23
Coagulation
factors
Anti-fibrinolytic
factors
Overeating, inactivity
(acquired / genetic)
Liver
Muscle
Predisposition to atherothrombotic
vascular disease
Glucose
Type 2 diabetes
MODERN VIEW OF INSULIN RESISTANCE
Insulin resistance
VLDL
Courtesy of Yki-Järvinen H

24. 24

25. 25
(hepatic
lipase)
Fat Cells Liver
Kidney
Insulin
IR X
(CETP)
CE
 TG
 Apo B
 VLDL
(CETP)
HDL
(lipoprotein or hepatic lipase)
CETP:Cholesteryl Ester Transfer Protein
sLDLLDL
TG
Apo A-1
TGCE
FFA
VLDL
Mechanisms of IR – Dyslipidemia

26. 26

27. 27
INSULIN RESISTANCE &
HYPERTENSION
 #Hypertension is present in 42% of males and 38% of
females with a BMI of >30 kg/m2.
 Insulin is a stimulator of the vasodilator nitric oxide (NO) through insulin-mediated PI3K
signaling and phosphorylation of eNOS. Under normal circumstances, vasodilatation
occurs in the skeletal muscle vasculature in response to insulin release after eating and
promotes glucose disposal.
 endothelin-1 (ET-1) is a potent vasoconstrictor, which is stimulated by insulin activity.
No is an inhibitor of ET-1.
 In insulin-resistant states, insulin signaling through the PI3K pathway is impaired,
leading to decreased NO.
 In addition, increased cytokines, such as IL-6, along with low adiponectin levels and
leptin resistance, cause decreased NO and increased action of ET-1, with the
subsequent development of hypertension.
 FFA can also induce hypertension by increased production of ROS, which increase
oxidative stress and decrease NO.
 Hyperinsulinemia may also lead to increased peripheral vascular resistance due to
sympathetic overactivity, volume expansion from its antinatriuretic effects, and
increased antiotensinogen II. eNOS:Endothelial nitric oxide synthetase

28. 28
NO production
Vasoconstriction
Adapted from Steinberg H et al. Diabetes. 2000;49:1231.
Thiazolidinediones
IR
stress
Increased visceral fat
Increased lipolysis
Increased FFA levels
-
Endothelium
Increased TNF
-
Decreased adiponectin
-
FFA and Adipokines in ED
-

29. 29
IS LIVER FAT A CULPRIT OF DYSLIPIDEMIA?
Impaired insulin signalling via PI3 kinase enhances lipid transfer to
VLDL
Hepatic lipogenesis (liver fat) is regulated by SREBP-1c, ChREBP,
PPAR and LXR expression
Increases of apolipoprotein B stability and MTP activity
Hypoadiponectinemia via inhibition of AMP Kinase and PPARα
CHEBP:Charbohydrate Resonse Element Binding Protein
SREBP-1c:Sterol Regulatory element Binding Protein-1c
PPAR -:Peroxisome proliferator-activated receptor 
LXR:liver X receptors
Hepatic steatosis is a
key feature in diabetes
(69%) and dyslipidemia
(50%) {AASLDguidelines
2012}
75% of patients with D.M OR IGT
have M.S. {Harrison 2011}
Factors driving VLDL
assembly & hepatic release

30. 30

31. 31
Dyslipidemia and the Met.S
an inseparable couple?
Dyslipidemia is an early and
consistent component of insulin
resistance
Components of dyslipidemia
correlate with measurements of
insulin resistance
(HOMA-index)
Liver fat seems to be the unifying
factor between dyslipidemia and
insulin resistance

32. 32
Ethnicity and Insulin Sensitivity

33. 33
Can We Identify IR ?
Features Insulin Resistance
Hyperglycemia ↑ PPBG, Usually FBG is N
Obesity, ↑ WC BMI > 23, WC > 90
↑ TG, ↓ HDL, ↑ sLDL Dyslipidemia Present
Cluster of metabolic
factors
Metabolic Syndrome
Hypertension (>130/80) Usually is a feature
Recent weight change Increase
Fasting C peptide /
Insulin
Increased (HOMA)
Treatment Exercise, Sensitizers

34. 34
Measures of IR
 Can we measure insulin resistance ? Yes !
 Fasting C-Peptide levels, FBG
 CISI – Composite Insulin Sensitivity Index
k (= 10,000) is a constant that provides numbers that are easy to deal with, G0 and G120
represent the plasma glucose concentrations at times 0 and 120 min, I0 and I120 represent the
plasma insulin concentrations at times 0 and 120 min, and sqrt is the mathematical function
to calculate the square root.
 QUICKI – Quantitative Insulin Sensitivity Index=
(1/log insulin + log glycemia in mg/dl)
 HOMA IR – Homeostasis Model Assessment
Fasting serum insulin (µu/ml) x fasting plasma glucose (mmol/l) /22.5
{normal up to 2} high value=IR
 HOMA calculator is available HOMA Calculator v2.2.LNK

35. 35
ABDOMINAL
OBESITY

36. 36
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

37. 37
• What is Abdominal Obesity ?
• Can be defined by Waist Circumference;
ATP- III (2002) IDF (2006)
Male:
> 102 Cm. (> 42 Inch )
Female :
> 88 Cm. (> 35 Inch )
Male :
> 94 Cm. ( > 37 Inch )
Female :
> 80 Cm. ( > 31.5 Inch )
WHO:
Waist-hip ratio >0.9 (men) or >0.85 (women)

38. 38
Ethnic specific values for waist
circumference (IDF)
• Europeans Male ≥ 94 cm Female ≥ 80 cm
• South Asians Male ≥ 90 cm Female ≥ 80 cm
• Chinese Male ≥ 90 cm Female ≥ 80 cm
• Japanese Male ≥ 85 cm Female ≥ 90 cm
• Ethnic South and Central Use South Asian
recommendations until more specific
• Americans data are available (ATPIII)
• Eastern Mediterranean and Middle East (Arab)
populations Use European data until more specific
data are available

39. 39
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

40. 40
Targeting Cardiometaboilc Risk
86% At least 1 additional CM risk factor
24% 2 or more additional CM risk factors
Abdominally
obese
patients

41. 41

42. 42
Abdominal obesity and increased
risk of cardiovascular events
Dagenais GR et al, 2005
Adjustedrelativerisk
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

43. 43
Abdominal obesity predicts adverse
outcomes such as sudden death
Quintile of SAD
The Paris Prospective study
Empana JP et al, 2004
Quintile 1 2 3 4 5
SAD (cm) 12–19 20–21 22–23 24 25–35
BMI (kg/m2) <23.2 23.2–24.9 25.0–26.6 26.7–28.4 28.5–47.7
1
0
2
3
4
1 2 3 4 5
1
0
2
3
4
1 2 3 4 5
Age-adjusted
relativerisk
Age-adjusted
relativerisk
Quintile of BMI
p for trend
=0.0003
SAD is a better
predictor of
risk of sudden
death than BMI
SAD: sagittal abdominal diameter; BMI: body mass index

44. 44
Intra-abdominal adiposity
and dyslipidaemia
Pouliot MC et al, 1992
310
248
186
124
62
0
60
45
30
mg/dL
mg/dL
Triglycerides
Lean
HDL-cholesterol
Visceral fat
(obese subjects)
Low High Lean
Visceral fat
(obese subjects)
Low High
HDL: high-density lipoprotein

45. 45

46. 46
Pouliot MC et al, 1992
IAA: intra-abdominal adiposity; significantly different from 1non-obese, 2obese
with low intra-abdominal adiposity levels
Non-obese Obese low IAA Obese high IAA
Time (min) Time (min)
1
1
1
1
1
1,2
1
1
1
mmol/L
0
3
6
9
12
15
0 60 120 180
1,2
0
400
800
1200
1,2
1,2
1,2 1,2
1,2
1,2
1,2
1,2
1
Area
1,2
Area
0 60 120 180
pmol/L
InsulinGlucose
Intra-abdominal adiposity
and glucose metabolism

47. 47
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
Relativerisk
Waist circumference (cm)
Carey VJ et al, 1997

48. 48
Fat Topography In Type 2
Diabetic Subjects
Intramuscular
Intrahepatic
Subcutaneous
Intra-
abdominal
FFA*
TNF-alpha*
Leptin*
IL-6 (CRP)*
Tissue Factor*
PAI-1*
Angiotensinogen*

49. 49
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
2.44p for trend = 0.007
Relativerisk
Quintiles of waist circumference (cm)
Rexrode KM et al, 1998
CHD: coronary heart disease; BMI: body mass index

50. 50
Abdominal obesity: a major underlying
cause of acute myocardial infarction
Yusuf S et al, 2004
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
Cardiometabolic risk factors in the INTERHEART Study
PAR(%)a
Abdominal obesity predicts the
risk of CVD beyond BMI
0
20
40
60
18
Hypertension
10
Diabetes
20
Abdominal
obesity
49
Abnormal
lipids

51. 51
Intra-abdominal adiposity is closely
correlated with abdominal obesity
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
Després JP et al, 2001; Pouliot MC et al, 2004
300
200
100
0
r = 0.80
60 80 100 120
IAA
Waist circumference (cm)
IAA(cm2)
IAA: intra-abdominal adiposity; CT: computed tomography;
MRI: magnetic resonance imaging

52. 52
Measurement of Waist

53. 53
Waist Circumference

54. 54

55. 55

56. 56
Normal Visceral Adiposity
Courtesy of Wilfred Y. Fujimoto, MD.
Visceral Fat Distribution

57. 57
Diabetes in the new millennium
Interdisciplinary problem
Diabetes

58. 58
Diabetes in the new millennium
Interdisciplinary problem
OBESITY

59. 59
Diabetes in the new millennium
Interdisciplinary problem
DIAB
ESITY

60. 60

61. 61
Intra-abdominal adiposity is a major
contributor to increased
cardiometabolic risk
Kershaw EE et al, 2004; Lee YH et al, 2005;
Boden G et al, 2002
Associated with
inflammatory markers
(C-reactive protein)

Free fatty
acids
Inflammation
Insulin
resistance
Dyslipidaemia
Increased
cardiometabolic
risk
IAA = high risk fat
Secretion of
adipokines
(↓ adiponectin)

IAA: intra-abdominal adiposity

62. 62
Adiponectin
 in IAA
Anti-atherogenic/antidiabetic:
 foam cells  vascular remodelling
 insulin sensitivity  hepatic glucose output
IL-6
 in IAA
Pro-atherogenic/pro-diabetic:
 vascular inflammation  insulin signalling
TNF-
 in IAA
Pro-atherogenic/pro-diabetic:
 insulin sensitivity in adipocytes (paracrine)
PAI-1
 in IAA
Pro-atherogenic:
 atherothrombotic risk
IAA: intra-abdominal adiposity; IL-6: interleukin-6;
TNF-α: tumour necrosis factor-α; PAI-1: plasminogen activator inhibitor-1
Marette A, 2002
Properties of key adipokines

63. 63
Visceral fat – Adipocytokines
• Leptin – Satiety signal– Obesity
• Acylation Stimulation Protein (ASP) MS
• Adiponectin (protective) leads FFA – IR
• Resistin – Anti Insulin effects - IR
• TNF–alpha, IL-6 – Adipocytokine - FFA
• PPAR– –nuclear enzyme - Inflammation
• PAI-1 - Procoagulant, Anti fibrinolytic
• MCP-1 – Chemokine - Inflammatory
• FFA – IR – JNK mediated
PPAR -:Peroxisome proliferator-activated receptor 
PAI-1:plasminogen activator inhibitor -1
MCP-1:Monocyte chemoattractant protein-1
JNK-1:Jun N-terminal kinase 1(The target of JNK1 action is serine phosphorylation of IRS-1, which impairs
insulin Action)

64. 64
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

65. 65
Acanthosis Nigricans
In patients with Acanthosis Nigricans with or without
T2DM, not taking statins or lipid lowering agents check
their lipid panel, if their LDL and triglycerides are really
low think of cancer. The cancers of endothelium eat up
the cholesterol for energy.

66. 66
Acanthosis Nigricans

67. 67
Acanthosis Nigricans

68. 68
Acanthosis Nigricans

69. 69
PCOS – Insulin Resistance
IR and
Obesity
Endocrine
Liver
SHBG
Ovary
Androgen
Adrenal
Androgen
Metabolic
MS, DM
PCOS, Infertility,
Irr. Menses, Hirsutism CVD

70. 70
PCOS
 Ovarian dysfunction in 6-10% of pre-menopausal
 Amenorrhea, oligomenorrhea, dysmenorrhea
 Androgenic features - low pitched voice, hirsutism,
 Enlarged ovaries - multiple small cysts - PCOD
 Acne, infertility, seborrhea, Acanthosis, obesity, MS
 Elevated Luteinizing hormone, Low/normal FSH

71. Adult Treatment Panel III
(ATP III) Guidelines
National Cholesterol Education Program

72. ATP III Guidelines
Detection and Evaluation

73. 73
Categories of Risk Factors
• Major risk factors
• Life-habit risk factors
• Emerging risk factors

74. 74
Life-Habit Risk Factors
• Obesity (BMI  30)
• Physical inactivity
• Atherogenic diet
Emerging Risk Factors
• Lipoprotein (a)
• Homocysteine
• Prothrombotic factors
• Proinflammatory factors
• Impaired fasting glucose
• Subclinical atherosclerosis

75. 75
Risk Assessment
Count major risk factors
• For patients with multiple (2+) risk factors
– Perform 10-year risk assessment
• For patients with 0–1 risk factor
– 10 year risk assessment not required
– Most patients have 10-year risk <10%

76. 76

77. 77
Major Risk Factors (Exclusive of LDL
Cholesterol) That Modify LDL Goals
• Cigarette smoking
• Hypertension (BP 140/90 mmHg or on
antihypertensive medication)
• Low HDL cholesterol (<40 mg/dL)†
• Family history of premature CHD
– CHD in male first degree relative <55
years
– CHD in female first degree relative <65
years
• Age (men 45 years; women 55 years)
† HDL cholesterol 60 mg/dL counts as a “negative” risk factor; its
presence removes one risk factor from the total count.

78. 78
CHD Risk Equivalents
• Risk for major coronary events equal to that
in established CHD
• 10-year risk for hard CHD >20%
Hard CHD = myocardial infarction + coronary death
Diabetes as a CHD Risk
Equivalent
• 10-year risk for CHD  20%
• High mortality with established CHD
– High mortality with acute MI
– High mortality post acute MI

79. 79
CHD Risk Equivalents
• Other clinical forms of atherosclerotic disease
(peripheral arterial disease, abdominal aortic
aneurysm, and symptomatic carotid artery
disease)
• Diabetes
• Multiple risk factors that confer a 10-year risk
for CHD >20%

80. 80
ATP III Lipid and
Lipoprotein Classification
LDL Cholesterol (mg/dL)
<100 Optimal
100–129 Near optimal/above
optimal
130–159 Borderline high
160–189 High
190 Very high

81. 81
ATP III Lipid and
Lipoprotein Classification (continued)
HDL Cholesterol
(mg/dL)
<40 Low
60 High

82. 82
ATP III Lipid and
Lipoprotein Classification (continued)
Total Cholesterol (mg/dL)
<200 Desirable
200–239 Borderline high
240 High

83. 83
Abdominal
Obesity Insulin
Resistance
Lipids and
BP control
Cardiometabolic Risk Reduction

84. 84
Management of MS
Primary Secondary Drug Rx
Total Lifestyle
Calorie restriction
Physical Activity
Change in Diet
 TG, sLDL
 LDL & Apo B
 HDL
Attain goal BP
PPAR -Fibrates
Statins full dose
Niacin, Aspirin
ACE/ARB, other

85. ATP III Guidelines
Goals and Treatment
Overview

86. 86
Primary Prevention With
LDL-Lowering Therapy
Public Health Approach
• Reduced intakes of saturated fat and
cholesterol
• Increased physical activity
• Weight control
Goals of Therapy
• Long-term prevention (>10 years)
• Short-term prevention (10 years)

87. 87
Causes of Secondary
Dyslipidemia
• Diabetes
• Hypothyroidism
• Obstructive liver disease
• Chronic renal failure
• Drugs that raise LDL cholesterol and lower
HDL cholesterol (progestins, anabolic
steroids, and corticosteroids)

88. 88
Secondary Prevention With
LDL-Lowering Therapy
• Benefits: reduction in total mortality,
coronary mortality, major coronary events,
coronary procedures, and stroke
• LDL cholesterol goal: <100 mg/dL
• Includes CHD risk equivalents
• Consider initiation of therapy during
hospitalization
(if LDL 100 mg/dL)

89. 89
LDL Cholesterol Goals and Cutpoints for
Therapeutic Lifestyle Changes (TLC)
and Drug Therapy in Different Risk Categories
Risk Category
LDL Goal
(mg/dL)
LDL Level at Which
to Initiate
Therapeutic
Lifestyle Changes
(TLC) (mg/dL)
LDL Level at Which
to Consider
Drug Therapy
(mg/dL)
CHD or CHD Risk
Equivalents
(10-year risk >20%)
<100 100
130
(100–129: drug
optional)
2+ Risk Factors
(10-year risk 20%) <130 130
10-year risk 10–
20%: 130
10-year risk <10%:
160
0–1 Risk Factor <160 160
190
(160–189: LDL-
lowering drug
optional)

90. ATP III Guidelines
Therapeutic Lifestyle
Changes (TLC)

91. 91
Therapeutic Lifestyle Changes in
LDL-Lowering Therapy
Major Features
• 1-Diet
– Reduced intake of cholesterol-raising nutrients
 Saturated fats <7% of total calories
 Dietary cholesterol <200 mg per day
– LDL-lowering therapeutic options
 Plant stanols/sterols (2 g per day)
 Viscous (soluble) fiber (10–25 g per day)
• 2-Increased physical activity”at least 30 min.of moderate
intensity daily activity ”swimming, walking, gardening,
housecleaning,....”

92. 92
Therapeutic Lifestyle Changes
Nutrient Composition of TLC Diet
Nutrient Recommended Intake
• Saturated fat Less than 7% of total calories
• Polyunsaturated fat Up to 10% of total calories
• Monounsaturated fat Up to 20% of total calories
• Total fat 25–35% of total calories
• Carbohydrate 50–60% of total calories
• Fiber 20–30 grams per day
• Protein Approximately 15% of total calories
• Cholesterol Less than 200 mg/day
• Total calories (energy) Balance energy intake and expenditure
to maintain desirable body weight/
prevent weight gain

93. 93
Therapeutic Lifestyle Changes in
LDL-Lowering Therapy ”continued”
3-Weight reduction:
 American College Of Sports Medicine recommends that
obese &overweight individuals should perform physical
exercise”at least 150 min.of modest intensity physical
activity per week to achieve effective weight loss”
 Behavioral therapy ”stress management,social support.....”
 Drugs:
Indications:BMI > 30 kg/m² or BMI > 27 kg/m² with
obesity-related disease or if dietary control
& physical execises were unsuccessful to
control weight.

94. 94
Phamacologic therapy for obesity
Centrally acting anorexiant agents:
(sibutramine=meridia®)
 It was the only anorexiant approved by FDA for long
term use.
 Produces average loss 5-9% of initial body weight at
12 mth.maintained upto 2 years.
 Inhibit serotonin & norepinephrine reuptake at the
level of hypothalamus,suppressing the appetite.
 Side effects:headache,
dry mouth,insomnia &
constipation.

95. 95
• Regular follow up of bl.pr. & H.R.is mandatory: dose of
10-15mg/day increases H.R.4-6 b/min & BP:2-4
mmHg
• Contraindications to sibutramine:
CHF,uncontrolled HTN, symptomatic CHD, arrhythmias
or history of stroke.
 On October 8, 2010 Abbott laboratories withdraw sibutramine
from the US market under pressure from the FDA, due to
increased risk of adverse cardiovascular events.
Peripherally acting anorexiants:
(orlistat=xenical®)
 Blocks digestion & absorption of 30% of dietary fat by
forming reversible covalent bonds with gastric,
pancreatic lipases & phospholipase A2 thus blocking
hydrolysis of fat into fatty acids & glycerol.

96. 96Side effects:fecal urgency,oily stool,...
vitamin A,D,E,K deficiencies.....so
should be supplemented.
• On 26 May 2010, FDA approved a revised label
for Xenical to include new safety information about
cases of severe liver injury that have been reported
rarely with the use of this medication.
Cannabinoid receptor antagonist
(rimonabant):
 suppress the motivation to find & consume food.
 Side effects:depression,anxiety & nausea.
 U.S. FDA in 2007 had voted not to recommend the drug's approval
because of concerns over suicidality, depression, and other related
side effects associated with use of the drug.
Bariatric surgery:
Indication: severe obesity BMI ≥ 40 kg/m² or
BMI ≥ 35 kg/m² associated with serious medical
condition.

97. 97
• Reinforce reduction
in saturated fat and
cholesterol
• Consider adding
plant stanols/sterols
• Increase fiber intake
• Consider referral to
a dietitian
• Initiate Tx for
Metabolic
Syndrome
• Intensify weight
management &
physical activity
• Consider referral
to a dietitian
6 wks 6 wks Q 4-6 mo
• Emphasize
reduction in
saturated fat &
cholesterol
• Encourage
moderate physical
activity
• Consider referral to
a dietitian
Visit I
Begin Lifestyle
Therapies
Visit 2
Evaluate LDL
response
If LDL goal not
achieved,
intensify LDL
Lowering Tx
Visit 3
•Evaluate LDL
response
•If LDL goal not
achieved,
consider adding
drug Tx
A Model of Steps in
Therapeutic Lifestyle Changes (TLC)
Monitor
Adherence
to TLC
Visit N

98. ATP III Guidelines
Drug Therapy

99. 99
i-HMG CoA Reductase Inhibitors
(Statins)
• Reduce LDL-C 18–55% & TG 7–30%
• Raise HDL-C 5–15%
• Major side effects
– Myopathy
– Increased liver enzymes
• Contraindications
– Absolute: liver disease
– Relative: use with certain drugs

100. 100
HMG CoA Reductase
Inhibitors (Statins)”continued”
Statin Dose Range
Lovastatin 20–80 mg
Pravastatin 20–40 mg
Simvastatin 20–80 mg
Fluvastatin 20–80 mg
Atorvastatin 10–80 mg
Cerivastatin 0.4–0.8 mg
For each doubling of statin dose,there is
only 6% additional lowering of LDL-C

101. 101
HMG CoA Reductase Inhibitors (Statins) (continued)
Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality
• Reduce coronary procedures (PTCA/CABG)
• Reduce stroke
• Reduce total mortality
Cholesterol absorption inhibitor “ezetimibe”
should be the second choice,it lowers LDL-C
by 15-20 %

102. 102
ii-Bile Acid Sequestrants
• Major actions
– Reduce LDL-C 15–30%
– Raise HDL-C 3–5%
– May increase TG
• Side effects
– GI distress/constipation
– Decreased absorption of other drugs
• Contraindications
– Dysbetalipoproteinemia
– Raised TG (>200 mg/dL)

103. 103
ii-Bile Acid Sequestrants”continued”
Drug Dose Range
Cholestyramine 4–16 g
Colestipol 5–20 g
Colesevelam 2.6–3.8 g
Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality

104. 104
iii-Nicotinic Acid
• Major actions
– Lowers LDL-C 5–25%
– Lowers TG 20–50%
– Raises HDL-C 15–35% ,dose related
• Side effects: flushing, hyperglycemia,
hyperuricemia, upper GI distress,
hepatotoxicity
• Contraindications: liver disease, severe
gout, peptic ulcer

105. 105
iii-Nicotinic Acid”continued”
Drug Form Dose Range
Immediate release 1.5–3 g
(crystalline)
Extended release 1–2 g
Sustained release 1–2 g
Demonstrated Therapeutic Benefits
• Reduces major coronary events
• Possible reduction in total mortality

106. 106
iv-Fibric Acids
Major actions
– Lower LDL-C 5–20% (with normal TG)
– May raise LDL-C (with high TG)
– Lower TG 20–50%
– Raise HDL-C 10–20%
• Side effects: dyspepsia, gallstones,
myopathy
• Contraindications: Severe renal or hepatic
disease

107. 107
Fibric Acids”continued”
Drug Dose
• Gemfibrozil 600 mg BID
• Fenofibrate 200 mg QD
• Clofibrate 1000 mg BID
Demonstrated Therapeutic Benefits
• Reduce progression of coronary lesions
• Reduce major coronary events

108. 108
Progression of Drug Therapy
in Primary Prevention
If LDL goal
not achieved,
intensify
LDL-lowering
therapy
If LDL goal not
achieved,
intensify drug
therapy or
refer to a lipid
specialist
Monitor
response
and
adherence
to therapy
• Start statin or
bile acid
sequestrant
or nicotinic
acid
• Consider
higher dose of
statin or add a
bile acid
sequestrant or
nicotinic acid
• Higher dose of statin
• Statin + bile acid
sequestrant
• Statin + nicotinic acid
6 wks 6 wks Q 4-6
mo
• If LDL goal achieved, treat
other lipid risk factors(if
present)
• High triglycerides (200 mg/dL)
• Low HDL cholesterol (<40 mg/dL)
Initiate
LDL-
lowering
drug
therapy
after 3
months of
lifestyle
therapies

109. 109
Secondary Prevention: Drug Therapy
for CHD and CHD Risk Equivalents
• LDL-cholesterol goal: <100 mg/dL
• Most patients require drug therapy
• First, achieve LDL-cholesterol goal
• Second, modify other lipid and non-lipid
risk factors

110. 110
Secondary Prevention: Drug Therapy
for CHD and CHD Risk Equivalents
(continued)
Patients Hospitalized for Coronary Events or
Procedures
• Measure LDL-C within 24 hours
• Discharge on LDL-lowering drug if LDL-C 130 mg/dL
• Consider LDL-lowering drug if LDL-C is 100–129 mg/dL
• Start lifestyle therapies simultaneously with drug

111. 111
BLOOD PRESSURE CONTROL
In patients with the metabolic syndrome
without diabetes, the best choice for the first
antihypertensive should usually be an ACE
inhibitor or an angiotensin II receptor
blocker, they appear to reduce the
incidence of new-onset type 2 diabetes.
 sodium-restricted diet enriched in fruits and
vegetables and low-fat dairy products should
be advocated for all patients.

112. 112
BLOOD SUGAR CONTROL
In patients with the metabolic syndrome and
type 2 diabetes, aggressive glycemic control
may modify fasting triglycerides and/or HDL
cholesterol.
In those patients with IFG without a diagnosis of
diabetes, a lifestyle intervention that includes
weight reduction, dietary fat restriction, and
increased physical activity has been shown to
reduce the incidence of type 2 diabetes.
Metformin has also been shown to reduce the
incidence of diabetes, although the effect was
less than that seen with lifestyle intervention

113. 113
INSULIN SENSITIZERS?!
[biguanides, thiazolidinediones (TZDs)]
 Both metformin and TZDs enhance insulin action
in the liver and suppress endogenous glucose
production. TZDs, but not metformin, also improve
insulin-mediated glucose uptake in muscle and
adipose tissue.
 Benefits of both drugs have also been seen in
patients with NAFLD and PCOS, and they have been
shown to reduce markers of inflammation and small
dense LDL. In general, the beneficial effects of
TZDs appear superior to those of metformin.

114. 114
What should I take home ?
 Metabolic syndrome is a hidden volcano
 Evaluate every one >25 years of age for M.S.
 One manifestation – screen for all the rest
 W.C. must be measured routinely like taking BP
 Remember M.S. is the “PRE” for T2DM and CVD
 We should not wait till these killers develop
 There are effective Rx strategies

115. 115

116. 116

117. Dr.Eslam Ahmed Habba-EAH2007@yahoo.comDr.Eslam Ahmed Habba-EAH2007@yahoo.com