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New Insights and Therapies for the Metabolic Syndrome. Thomas Alexander, M.D. New Features of ATP III. Identification of metabolic syndrome Abdominal obesity; men more than 40 inches; women more than 35 inches Triglycerides; >150 mg HDL cholesterol for men <40 mg; women <50 mg

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New Insights and Therapies for the Metabolic Syndrome

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new features of atp iii
New Features of ATP III
  • Identification of metabolic syndrome
    • Abdominal obesity; men more than 40 inches; women more than 35 inches
    • Triglycerides; >150 mg
    • HDL cholesterol for men <40 mg; women <50 mg
    • Blood pressure >130/85
    • Fasting glucose >110
definition of metabolic syndrome
Definition of Metabolic Syndrome
  • Insulin resistance
  • Life style especially obesity
  • Sub clinical inflammation
  • Diabetes and prior myocardial infarction carry the same mortality risk
risk factors not routinely measured
Risk Factors – Not routinely measured
  • Insulin resistance
  • Small dense LDL
  • Endothelial dysfunction
  • Abnormal sympathetic nervous activity
  • Prothrombotic markers – fibrinogen
  • Proinflamatory markers
features of diabetes mellitus
Features of Diabetes Mellitus
  • Hyperglycemia - Secondary to defect in insulin secretion or insulin action or both
  • Diagnosis – Fasting plasma glucose of 110 to 126 – pre diabetes
  • Blood sugar > 126 or plasma glucose > 200 on a GTT.
  • Type 1 Diabetes – β-cell destruction due to immune mediated or idiopathic
  • Type 2 Diabetes – with relative insulin deficiency to a predominant secretory defect with insulin resistance
  • Gestational
  • Genetic defects in β–cell function
  • Drug induced
  • Infections
type 1 diabetes mellitus
Type 1 Diabetes Mellitus
  • Insulin deficiency – secondary to β-cell destruction
  • Markers – islet cell auto antibodies, auto antibodies to insulin, auto antibodies to glutamic acid decarboxylase
type 2 diabetes mellitus
Type 2 Diabetes Mellitus
  • Has strong genetic predisposition
  • Obesity can cause some insulin resistance
  • Ketoacidosis seldom occurs
  • Hyperglycemia may develop gradually
  • At increase risk for micro & macro vascular complications
  • Increase levels of tumor necrosis factor-α and free fatty acids produce insulin resistance
progress of pathogenic type 2 diabetes mellitus
Progress of Pathogenic Type 2 Diabetes Mellitus

Initiation Factors Progression Factors

-Insulin resistance -Obesity

-Insulin secretion -β-cell Toxins

-β-cell capacity genes -Diet/toxins

-Obesity genes -Activity/age

Type 2 Diabetes

Failing insulin secretion, glucose desensitization of β-cell, decreased glucose sensitivity

treatment of diabetes mellitus type 2
Treatment of Diabetes Mellitus Type 2
  • Oral anti diabetic agents

1. Sulfonylureas and meglitinides – augment insulin levels

2. Metformin – inhibit hepatic gluconeogenesis and glycogenolysis, improve insulin sensitivity

3. Thiazolydinediones – suppress expression of specific genes & lower triglycerides

4. Acarbose – reduces absorption of CHO

5. Combination Therapy preferred

6. Insulin Therapy

  • Acute

-Diabetic ketoacidosis, dehydration, K depletion, cerebral edema, non ketotic hyperosmolar coma

  • Long Term

-Cardiovascular disease causes 75% of disabilities and deaths in diabetes caused by insulin resistance, hypertrigl: HTN, low HDL. Target LDL < 100, triglycerides < 150, HDL >50, BP < 130/80


-Micro vascular – diabetic retinopathy, nephropathy, neuropathy, cardiovascular autonomic neuro: GI neuro:

-Diabetic foot > 50% of all non traumatic complications in U.S. is secondary to diabetes

macro vascular complications
Macro Vascular Complications
  • Mortality from CVD 2 fold > in men 4 fold > in women
  • 7 yr incidence of MI = non DM with MI
  • Reduction in BP, reduced MI by 21% and stroke by 44%
  • Cholesterol lowering, reduced CVD by 24%
  • In secondary prevention reducing cholesterol, reduced CVD by 42%




-Dietary fat LDL

LDL Receptor

Intestine Extra,




Adipose tissue IDL

and muscle Capillary Plasma

FFA Adip: Tissue

Liver Endo: Chol:

Diet: Chol:

atp iii guidelines
ATP III Guidelines
  • Step 1

-Determine lipoprotein levels after 9 to 12 hour fast

-LDL Cholesterol – Primary target, <100 optimal, 100-129 near optimal, 130-159 borderline high, 160-189 high, >190 very high

-Total Cholesterol - <200 desirable, 200-239 borderline high, >240 High

-HDL Cholesterol - <40 low

Step 2

-Identify presence of atherosclerotic disease

-Clinical CHD

-Carotid artery disease



Step 3

-Determine major risk factors other than LDL

-Cigarette smoking

-Hypertension, BP >140/90

-Low HDL

-Family history of premature CHD

-Age, Men >45 & women >55

-HDL Cholesterol >60 – count as a negative risk factor

Step 4

- If 2+ risk factors (other than LDL) present without CHD assess 10 year CHD risk (see Framingham tables)

-Three levels of 10 year risk

- >20% - CHD risk equivalent

- 10 to 20%

- <10%

Step 5

-Determine risk category

-Establish LDL goal of therapy

-Determine need for therapeutic lifestyle changes

-Determine level for drug consideration

ldl cholesterol goals and cut points for tlc and drug therapy in different risk categories
LDL Cholesterol Goals and Cut points for TLC and Drug Therapy in different Risk Categories
Step 6

-Initiate TLC in LDL is above goal

-TLC Diet:

-Saturated fat <7% of calories, cholesterol <200 mg/day

-Weight management

-Increased physical activity

Step 7

-Consider drug simultaneously with TLC for CHD

-Consider adding drug to TLC after 3 months for other risk categories

Step 8

-Identify metabolic syndrome and treat after 3 months of TLC

Risk Factor Defining Level

Abdominal obesity Waist Circumference

Men >102 cm

Women >88 cm

Triglycerides > 150 mg/dL

HDL cholesterol

Men < 40 mg/dL

Women < 50 mg/dL

Blood Pressure > 130/ >85 mmHg

Fasting Glucose > 110mg/dL

Step 9

-Treat elevated triglycerides

ATP III Classification of Serum triglycerides

<150 Normal

150-199 Borderline

200-499 High

>500 Very high

Treatment of elevated triglycerides

-Reach LDL goal

-Intensify weight management

-Increase physical activity

Comparison of LDL Cholesterol & Non-HDL Cholesterol Goals for 3 risk Categories

If triglycerides 200-449 mg/dL after LDL goal is reached, consider adding drug if needed to reach non-HDL goal:

-intensify therapy with LDL-lowering drug

-add nicotinic acid of fibrate to further lower VLDL

If triglycerides >500 mg/dL, first lower triglycerides to prevent pancreatitis:

-very low-fat diet

-weight management and physical activity

-fibrate or nicotinic acid

When trigly. <500 mg/dL, turn to LDL-lowering therapy

Treatment of low HDL cholesterol

-First reach LDL goal

-Intensify weigh management and increase physical activity

-If trigly. 200-449 mg/dL, achieve non-HDL goal

-If trigly. <200 mg/dL in CHD or CHD equiv. consider nicotinic acid or fibrate.

diet for the metabolic syndrome
Diet for the Metabolic Syndrome
  • Primary emphasis is to reduce saturated fats
  • Total fat should range 25-30% for most cases
  • Those with metabolic syndrome avoid very high fat intake also avoid very low fat intake (low HDL & high TG)
  • Total fat intake can range from 30-35% if extra fat in unsaturated
  • May reduce some lipid and non lipid risk factors
  • Clinical judgment required