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New Feature of NCEP ATP III:* Identification 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 † )

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new feature of ncep atp iii identification of the metabolic syndrome
New Feature of NCEP ATP III:*Identification 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 >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

insulin resistance
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)
visceral obesity is associated with a cluster of metabolic abnormalities
Visceral obesity is associated with a cluster of metabolic abnormalities
metabolic syndrome total and cv mortality in middle aged men in kuopio heart study
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

4

8

10

12

6

0

2

4

6

8

10

12

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

role of peroxisome proliferator activated receptors
ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS
  • PPARs—Steroid 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
oral agents for type 2 diabetes primary sites of action

ImpairedInsulinSecretion

InsulinDeficiency

=

 GlucoseUptake

InsulinResistance

=

Oral Agents for Type 2 Diabetes: Primary Sites of Action

Sulfonylureas

Repaglinide

Acarbose

Miglitol

Gut

Pancreas

CarbohydrateMetabolism

Hyperglycemia

 Hepatic Glucose Production

Muscle

Liver

Rosiglitazone

Pioglitazone

Metformin

ppar gamma activators glitazones
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
established modifiable cv risk factors in t2dm
Position in Model Variable P Value*

First Low-density lipoprotein cholesterol <0.0001

Second High-density lipoprotein cholesterol 0.0001

Third Hemoglobin A1c 0.0022

Fourth Systolic blood pressure 0.0065

Fifth Smoking 0.056

Established Modifiable CV Risk Factors in T2DM

UKPDS 23: CAD

effect of glycemic control in the uk prospective diabetes study ukpds
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

effect of blood pressure control in the ukpds tight vs less tight control
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

ukpds comparison between tight control of bp and glycemia on risk of diabetes complications
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%)

major outcomes of the hypertension optimal treatment hot trial diabetes subgroup
Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup

Diastolic Target

p<0.005

<90 mmHg (N=501)

<85 mmHg (N=501)

<80 mmHg (N=499)

Events / 1000 Pt-Years

p<0.016

p<0.045

Major CV Events

MI

CV Mortality

Hansson L et al. Lancet 1998;351: 1755-1762.

slide19

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

DiabeticPatients

NondiabeticPatients

N=3,578, P=<0.001

N=5,719, P=<0.001

micro hope ramipril significantly reduces cardiovascular morbidity

Nonfatal

MI

CV

Death

Total

Mortality

Stroke

0

-5

-10

-15

Risk Reduction (%)

-20

22%

-25

*P = 0.0074

†P = 0.01

‡P = 0.0001

§P = 0.0004

24%

§

-30

-35

33%

*

-40

37%

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
evolving science central role of ang ii in atherosclerosis
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

slide23
Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Trialists’ Collaboration

P<0.002

Antiplatelet Therapy Control

P<0.00001

CVD Events (%)

Diabetes

No Diabetes

chd incidence by hba 1c levels in type 2 diabetic subjects
CHD Incidence by HbA1c Levels in Type 2 Diabetic Subjects

HbA1c tertile

Low <6%

Middle 6% to 7.9%

High >7.9%

25

20

Incidence (%) in 3.5 y

*

15

10

5

0

All CHD Events

CHD Mortality

*P<0.01 vs. lowest tertile; †P<0.05 vs. lowest tertile; n=229 men and women.

Patients 65–74 years old with T2DM at baseline.

collaborative atorvastatin diabetes study cards
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

cards cumulative hazard for primary endpoint

15

10

5

0

0

1

2

3

4

4.75

CARDS:Cumulative Hazard for Primary Endpoint

Relative Risk Reduction 37% (95% CI: 17-52)

P=0.001

Placebo

127 events

Cumulative Hazard (%)

Atorvastatin

83 events

Years

Placebo

1410

1351

1306

1022

651

305

Atorva

1428

1392

1361

1074

694

328

cards treatment effect on the primary endpoint

Event

Placebo*

Atorva*

Hazard Ratio Risk Reduction (CI)

Primary endpoint

127 (9.0%)

83 (5.8%)

37% (17-52)

p=0.001

Acute coronary events

77 (5.5%)

51 (3.6%)

36% (9-55)

Coronary revascularisation

34 (2.4%)

24 (1.7%)

31% (-16-59)

Stroke

39 (2.8%)

21 (1.5%)

48% (11-69)

CARDS: Treatment Effect on the Primary Endpoint

.2

.4

.6

.8

1

1.2

* N (% randomised)

Favours Atorvastatin Favours

Placebo

prevention of diabetic atherothrombosis
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