New Feature of NCEP ATP III:* Identification of the Metabolic Syndrome - PowerPoint PPT Presentation

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New Feature of NCEP ATP III:* Identification of the Metabolic Syndrome

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Men 102 cm ( 40 in) Women 88 cm ( 35 in) Triglycerides ... Expressed throughout vasculature; limits adhesion molecule expression,tissue factor production ... – PowerPoint PPT presentation

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Title: New Feature of NCEP ATP III:* Identification of the Metabolic Syndrome


1
New Feature of NCEP ATP IIIIdentification of
the Metabolic Syndrome
Positive diagnosis based on the presence of
three or more of the following
Risk Factor
Defining Level
Abdominal obesity (waist
circumference ) Men
gt102 cm (gt40 in)
Women
gt88 cm (gt35 in) Triglycerides
?150 mg/dL
HDL cholesterol
Men lt40
mg/dL Women
lt50 mg/dL Blood
pressure ?130/?85 mm Hg
Fasting glucose ?110
mg/dL
2
INSULIN RESISTANCE
  • An impaired biological response to insulin
  • Resistance to insulin-stimulated glucose uptake
  • An impairment of normal glucose uptake by muscle
  • Unregulated overproduction of glucose by the
    liver
  • Core defect in T2DM
  • Underlying defect in the metabolic syndrome
    (clinical picture)

3
Visceral obesity is associated with a
cluster of metabolic abnormalities
4
Metabolic Syndrome Total and CV Mortality in
Middle-Aged Men in Kuopio Heart Study
Cardiovascular Disease Mortality
All-Cause Mortality
Metabolic Syndrome
Metabolic Syndrome
20
20
Yes
RR (85 CI)3.55 (1.96-6.43)
RR (85 CI)2.13 (1.64-3.61)
15
15
Cumulative Hazard ()
10
10
Yes
No
5
5
No
No. at Risk MetabolicSyndrome
0
0
0
2
8
10
12
4
6
0
2
8
10
12
4
6
Follow-up (Years)
Follow-up (Years)
Yes 866 852 834 292 No 288 279 234 100
Yes 866 852 834 292 No 288 279 234 100
5
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6
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7
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8
ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED
RECEPTORS
  • PPARsSteroid hormone nuclear receptors
  • Act as ligand-activated transcription factors
  • Control expression of specific target genes
  • Protein products control a variety of cellular
    functions
  • PPAR-alpha family is a critical regulator of
    fatty acid metabolism
  • Expressed throughout vasculature limits adhesion
    molecule expression,tissue factor production
  • PPAR-gamma family plays central role in fatty
    tissue production,fat metabolism,glucose
    regulation
  • Highly expressed in endothelial cells,smooth
    muscle cells,lymphocytes,macrophages

9
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10
PPARa regulates Apo A-I, Apo A-II, LPL, ABCA-1
and SR-BI expression
11
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12
Oral Agents for Type 2 Diabetes Primary Sites
of Action
Acarbose Miglitol
Sulfonylureas Repaglinide
Gut
Pancreas
CarbohydrateMetabolism
Hyperglycemia
? Hepatic Glucose Production
Muscle
Liver
Rosiglitazone Pioglitazone
Metformin
13
PPAR-GAMMA ACTIVATORS (glitazones)
  • Reduce plaque inflammation
  • Inhibit expression of adhesion molecules and
    cytokines
  • Reduce production of Matrixmetalloproteinases
  • Reduce thrombogenicity and enhance fibrinolysis
  • Enhance reverse cholesterol transport and reduce
    cholesterol content of plaque

14
Established Modifiable CV Risk Factors in T2DM
UKPDS 23 CAD
  • Position in Model Variable P
    Value
  • First Low-density lipoprotein
    cholesterol lt0.0001
  • Second High-density lipoprotein cholesterol
    0.0001
  • Third Hemoglobin A1c 0.0022
  • Fourth Systolic blood pressure 0.0065
  • Fifth Smoking 0.056

15
Effect of Glycemic Control in the UK Prospective
Diabetes Study (UKPDS)
Intensive
Conventional
Decrease
(rate/1000 pt yrs)
(rate/1000 pt yrs)
Endpoints
P
Any diabetes related MI Stroke PVD Microvascular
0.029 0.052 0.52 0.15 0.0099
11 16 25
46 17.4 5 1.6 11.4
40.9 14.7 5.6 1.1 8.6
Combined microvascular and macrovascular events
16
Effect of Blood Pressure Control in the
UKPDS Tight vs. Less Tight Control
  • 1,148 Type 2 patients
  • Average BP lowered to 144/82 mmHg (controls
    154/87) 9-year follow-up

Risk Reduction ()
P value
Tight Control
Any diabetes-related endpoint Diabetes-related
deaths Heart failure Stroke Myocardial
infarction Microvascular disease
24 32 56 44 21 37
0.0046 0.019 0.0043 0.013 NS 0.0092
17
UKPDS Comparison Between Tight Control of BP
and Glycemia on Risk of Diabetes
Complications
Any Diabetes-related Outcome
Diabetes-related Death
Retino-pathy
Micro-vascular
Stroke
CHF
0
10
20
30

40
50
60
Tight BP (144/82 vs 154/87 mmHg) Tight glucose
(HbA1c 7 vs 7.9)
18
Major Outcomes of the Hypertension Optimal
Treatment (HOT) Trial Diabetes Subgroup
Diastolic Target
plt0.005
lt90 mmHg (N501) lt85 mmHg (N501) lt80 mmHg (N499)
Events / 1000 Pt-Years
plt0.016
plt0.045
Major CV Events
MI
CV Mortality
Hansson L et al. Lancet 1998351 1755-1762.
19
Heart Outcomes Prevention Evaluation (HOPE)
Study Effect of Ramipril on
Cardiovascular Events (Myocardial
Infarction, Stroke, or CVD Death) 4.5 Yrs
24 RiskReduction
21 RiskReduction
19.8
16.4
15.0
of Patients
13.0
Placebo
Ramipril
Placebo
Ramipril
Diabetic Patients
Nondiabetic Patients
N3,578, Plt0.001
N5,719, Plt0.001
20
MICRO-HOPE Ramipril Significantly Reduces
Cardiovascular Morbidity
Ramipril Effects Beyond Baseline Therapy
Aspirin Other Antiplatelet Agents
Lipid-Lowering Agents
Diuretics Beta-Blockers
Calcium-Channel Blockers
21
Angina and Coronary Artery Disease in Patients
with Diabetes Mellitus
22
Evolving Science Central Role of Ang II in
Atherosclerosis
Inflammation
EndothelialDysfunction
Lipid Oxidation
IL-5MCP-1PDGF
LOX-1
ImpairedNO synthase
VCAMICAM
Thrombosis
Angiotensin II
PAI-1TF
Adhesion
Angiotensin
TGF-b
ProliferationFibrosis
Autostimulation
23
Antiplatelet Agents Reduce CVD Events in Patients
with Diabetes Antiplatelet Trialists
Collaboration
Plt0.002
Antiplatelet Therapy Control
Plt0.00001
CVD Events ()
Diabetes
No Diabetes
24
CHD Incidence by HbA1c Levels in Type 2 Diabetic
Subjects
HbA1c tertile Low lt6 Middle 6 to 7.9
High gt7.9
25

20

Incidence () in 3.5 y
15
10
5
0
All CHD Events
CHD Mortality
Plt0.01 vs. lowest tertile Plt0.05 vs. lowest
tertile n229 men and women. Patients 6574
years old with T2DM at baseline.
25
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26
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27
COLLABORATIVE ATORVASTATIN DIABETES STUDY
(CARDS)
To evaluate the effectiveness and safety of
atorvastatin 10mg daily versus placebo in the
primary prevention of cardiovascular disease
(major coronary events, revascularisation and
stroke) in patients with type 2 diabetes without
raised cholesterol levels
28
CARDSCumulative Hazard
for Primary Endpoint
Relative Risk Reduction 37 (95 CI 17-52)
P0.001
Placebo 127 events
Cumulative Hazard ()
Atorvastatin 83 events
Years
305
651
1022
1306
1351
Placebo
1410
328
694
1074
1361
1392
Atorva
1428
29
CARDS Treatment Effect
on the Primary Endpoint
.2
.4
.6
.8
1
1.2
N ( randomised)
Favours Atorvastatin Favours

Placebo
30
Antiatherogenic Actions of Statins
? Expression of adhesion molecules ? Tissue
factor expression ? Endothelial NOS III ? O2
production ? Vascular A-II levels Anti-inflammator
y effects (? CRP)
  • ? Cholesterol esterification, LDL oxidation,
    macrophage uptake of oxLDL
  • ? SMC proliferation and/or migration
  • ? Monocyte-endothelial cell adhesion


31
PREVENTION OF DIABETIC ATHEROTHROMBOSIS
  • Aggressive treatment of at-risk patients should
    be pursued, following the latest guideline
    recommendations
  • Lipid lowering reduces clinical events and
    appears to stabilize plaque
  • ACE inhibitors reduce clinical events and may
    have antiatherosclerotic actions
  • Anti-platelet agents prevent thrombotic events
  • Glycemic control is effective in reducing risk of
    microvascular events and coronary events
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