New Insights and Therapies for the Metabolic Syndrome

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New Insights and Therapies for the Metabolic
Syndrome

Thomas Alexander, M.D.
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New Features of ATP III

• Identification of metabolic syndrome
• Abdominal obesity men more than 40 inches women
  more than 35 inches
• Triglycerides gt150 mg
• HDL cholesterol for men lt40 mg women lt50 mg
• Blood pressure gt130/85
• Fasting glucose gt110

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Definition of Metabolic Syndrome

• Insulin resistance
• Life style especially obesity
• Sub clinical inflammation
• Diabetes and prior myocardial infarction carry
  the same mortality risk

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Risk Factors Not routinely measured

• Insulin resistance
• Small dense LDL
• Endothelial dysfunction
• Abnormal sympathetic nervous activity
• Prothrombotic markers fibrinogen
• Proinflamatory markers

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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 gt 126 or plasma glucose gt 200 on a
  GTT.

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Etiology

• Type 1 Diabetes ß-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 ßcell function
• Drug induced
• Infections

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Type 1 Diabetes Mellitus

• Insulin deficiency secondary to ß-cell
  destruction
• Markers islet cell auto antibodies, auto
  antibodies to insulin, auto antibodies to
  glutamic acid decarboxylase

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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-a and
  free fatty acids produce insulin resistance

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Progress of Pathogenic Type 2 Diabetes Mellitus

• Initiation Factors Progression Factors
• -Insulin resistance -Obesity
• -Insulin secretion -ß-cell Toxins
• -ß-cell capacity genes -Diet/toxins
• -Obesity genes -Activity/age

Type 2 Diabetes
Failing insulin secretion, glucose
desensitization of ß-cell, decreased glucose
sensitivity
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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

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Complications

• 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 lt 100, triglycerides lt 150, HDL gt50,
  BP lt 130/80
• -PVD
• -Micro vascular diabetic retinopathy,
  nephropathy, neuropathy, cardiovascular autonomic
  neuro GI neuro
• -Diabetic foot gt 50 of all non traumatic
  complications in U.S. is secondary to diabetes

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Macro Vascular Complications

• Mortality from CVD 2 fold gt in men 4 fold gt 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

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Hyperlypoproteinemia
Exo
Endo

• LDL
• -Dietary fat
  LDL
• 
  LDL Receptor
• Intestine
  Extra,
• 
  Tissue
• Capillary
  
• FFA Remnants VLDL
  HDL
• Adipose tissue
  IDL
• and muscle
  Capillary Plasma
• 
  FFA Adip Tissue

Liver Endo Chol Diet Chol
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ATP III Guidelines

• Step 1
• -Determine lipoprotein levels after 9 to 12 hour
  fast
• -LDL Cholesterol Primary target, lt100 optimal,
  100-129 near optimal, 130-159 borderline high,
  160-189 high, gt190 very high
• -Total Cholesterol - lt200 desirable, 200-239
  borderline high, gt240 High
• -HDL Cholesterol - lt40 low

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• Step 2
• -Identify presence of atherosclerotic disease
• -Clinical CHD
• -Carotid artery disease
• -PVD
• -AAA

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• Step 3
• -Determine major risk factors other than LDL
• -Cigarette smoking
• -Hypertension, BP gt140/90
• -Low HDL
• -Family history of premature CHD
• -Age, Men gt45 women gt55
• -HDL Cholesterol gt60 count as a negative risk
  factor

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• 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
• - gt20 - CHD risk equivalent
• - 10 to 20
• - lt10

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• Step 5
• -Determine risk category
• -Establish LDL goal of therapy
• -Determine need for therapeutic lifestyle
  changes
• -Determine level for drug consideration

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LDL Cholesterol Goals and Cut points for TLC and
Drug Therapy in different Risk Categories
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• Step 6
• -Initiate TLC in LDL is above goal
• -TLC Diet
• -Saturated fat lt7 of calories,
  cholesterol lt200 mg/day
• -Weight management
• -Increased physical activity

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• Step 7
• -Consider drug simultaneously with TLC for CHD
• -Consider adding drug to TLC after 3 months for
  other risk categories

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Drugs Affecting Lipoprotein Metabolism
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• Step 8
• -Identify metabolic syndrome and treat after 3
  months of TLC
• Risk Factor
  Defining Level
• Abdominal obesity
  Waist Circumference
• Men
  gt102 cm
• Women
  gt88 cm
• Triglycerides
  gt 150 mg/dL
• HDL cholesterol
  
• Men
  lt 40 mg/dL
• Women
  lt 50 mg/dL
• Blood Pressure
  gt 130/ gt85 mmHg
• Fasting Glucose
  gt 110mg/dL

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• Step 9
• -Treat elevated triglycerides
• ATP III Classification of Serum triglycerides
• lt150 Normal
• 150-199 Borderline
• 200-499 High
• gt500 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

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• 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 gt500 mg/dL, first lower
  triglycerides to prevent pancreatitis
• -very low-fat diet
• -weight management and physical activity
• -fibrate or nicotinic acid
• When trigly. lt500 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. lt200 mg/dL in CHD or CHD equiv.
  consider nicotinic acid or fibrate.

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Estimate of 10 yr Risk for Men (Framingham Point
Scores)
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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

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• QUESTIONS????