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3. COMPOSITION OF VARIOUS LIPOPROTEINS & APOPROTEIN THEY CARRY
LIPOPROTEINS CORE LPIDS APOPROTEINS
CHYLOMICRONE TG>CE B 48, C, E, A
CHYLOMICRONE REMNANT TG<CE -DO-
VLDL TG>CE C, B 100, E
IDL TG=CE -DO-
LDL CE B 100
HDL CE (+PHOSPHOLIPIDS) A,C,E
4. TYPES OF HYPERLIPOPROTEINAEMIA
TYPE
ELEVATION IN
LIPROTEIN
ELEVATION IN
LIPIDS
RISK OF
ATHEROSC
LEROSIS
CAUSE
TG CH
I CM +++ +/N NO Absence of Lipoprotein Lipase
IIa LDL N ++ HIGH Deficiency of LDL-Receptor
IIb VLDL & LDL ++ ++ HIGH
Deficiency of LDL-Receptor
Overproduction of VLDL
III
REMNANT OF
VLDL & CM ++ ++ MODRATE
Mutant Apo-E (overproduction OR
Under utilization of IDL)
IV VLDL +++ +/N MODRATE
overproduction / Decrease Removal of VLDL
Patient- obese, diabetic, IHD, Most are
alcoholic, Normal-LDL
V VLDL & CM ++ +/N NO
Overproduction / Decrease clearance of VLDL
& CM (Rare, Genetic ,Normal-LDL)
7. EFFECT OF VARIOUS DRUG ON LIPIDS
• Alcohol -↑ 0 ↑
• Androgens -↑ ↑ ↓
• Testosterone -↑ ↑ ↓
• ACE-inhibitors -0 0 0
• Beta-blockers -↑ 0 ↓
• CCBs -0 0 0
• Ciclosporin -↑ ↑ ↑
• Oestrogens, Oestradiol -↑ ↓ ↓
• Glucocorticoids -↑ 0 ↑
• Isotretinoin -↑ 0 ↓
• Progestins -↓ ↑ ↓
• Protease Inhibitors- ↑ 0 0
• Sertraline- ↑ ↑ 0
• Tacrolimus- ↑ ↑ ↑
• Thiazide Diuretics -↑ ↑ ↓
• Valproate- ↑ 0 ↓
Drug - VLDL-C LDL-C HDL-C
Effect seen may vary depending on dose, duration of exposure and drugs within same class.
8. CLINICAL PRESENTATION
GENERAL
• Most patients are asymptomatic for many years prior to clinically evident disease.
• Patients with the metabolic syndrome may have three or more of the following:
abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance -
glucose intolerance, prothrombotic state, or proinflammatory state.
SYMPTOMS
• None to chest pain, palpitations, sweating, anxiety, shortness of breath, loss of
consciousness or difficulty with speech or movement, abdominal pain, sudden death.
SIGNS
• None to abdominal pain, pancreatitis, eruptive xanthomas, peripheral polyneuropathy,
high blood pressure, body mass index >30 kg/m 2 or waist size >40 inches in men (35
inches in women).
9. CLINICAL PRESENTATION
MAJOR RISK
AGE
Men: ≥45 years
Women: ≥55 years/premature menopause without estrogen replacement therapy
Family history of premature CHD
(definite MI or sudden death before 55 years of age in father or other male first-degree
relative, or before 65 years of age in mother or other female first-degree relative)
Cigarette smoking
Hypertension (≥140/90 mm Hg or on antihypertensive medication)
Low HDL cholesterol (<40 mg/dL) b
10. DIAGNOSIS
LABORATORY TESTS
• Elevation in following
Total cholesterol
LDL
Triglycerides
Apolipoprotein B,
C-reactive protein (CRP)
• Low HDL
OTHER DIAGNOSTIC TESTS
• Lipoprotein (a)
• Small, dense LDL (pattern B)
• HDL subclassification
• Apolipoprotein E isoforms
• Apolipoprotein A-1
• Fibrinogen
• Folate
• Lipoprotein-associated phospho –
lipase A2 .
• Various screening tests for
manifestations of vascular disease
• ankle-brachial index
• exercise testing
• magnetic resonance imaging
• Diabetes (fasting glucose, oral glucose
tolerance test, hemoglobin A 1c).
11. DIAGNOSIS
• Measure fasting lipoprotein profile (total CH, LDL, HDL, TGs) in all adults 20 years of
age or older at least once every 5 years.
• Measure plasma cholesterol, TGs & HDL levels after a 12-hour fast because TGs may be
elevated in non-fasting individuals. Total cholesterol is only modestly affected
• Two determinations, 1 to 8 weeks apart are recommended to minimize variability and
obtain a reliable baseline.
If the total cholesterol is greater than 200 mg/Dl (>5.17 mmol/L), a second
determination is recommended, and if the values are greater than 30 mg/dL (>0.78
mmol/L) apart, use the average of three values.
12. DIAGNOSIS
• Lipoprotein electrophoresis is sometimes performed to determine which class of
lipoproteins is involved.
If the triglycerides are less than 400 mg/dL (4.52 mmol/L), and neither type III
dyslipidemia nor chylomicrons are detected by electrophoresis,
then
one can calculate VLDL and LDL concentrations:
LDL = total cholesterol – (VLDL + HDL)
ratio of cholesterol toTGs in LDL is 1:5
LDL-C = Total Cholesterol − (HDL-C + TG/5)
Initial testing uses total cholesterol for case finding, but subsequent management
decisions should be based on LDL.
13. DIAGNOSIS
FOR DIABETIC PATIENTS
Once the TC, HDL-C and triglyceride values are known; value for LDL-C can be calculated
by Friedewald equation
LDL-C = (Total cholesterol - HDL-C) - (0.45 x triglyceride) mmol/L
It should not be used in non-fasting individuals (diabetic patient)
Not reliable for diabetic patient with triglyceride level >4 mmol/L.
LDL-C = Total Cholesterol − (HDL-C + TG/5)
ratio of cholesterol toTGs in LDL is 1:5
14. DIAGNOSIS
• History and physical examination should assess:
presence or absence of CV risk factors or definite CV disease
family history of premature CV disease or lipid disorders;
presence or absence of secondary causes of dyslipidemia, including concurrent
medications
Presence or absence of xanthomas, abdominal pain, or history of pancreatitis, renal or
liver disease, peripheral vascular disease, abdominal aortic aneurysm, or cerebral
vascular disease (carotid bruits, stroke, or transient ischemic attack).
• Diabetes mellitus and the metabolic syndrome are considered CHD risk equivalents;
their presence in patients without known CHD is associated with the same level of risk
as patients without them but having confirmed CHD.
15. The National Cholesterol Education Program Adult Treatment Panel III
(NCEP ATPIII) guideline is followed for ADULTS and children
TOTAL CHOLESTEROL
• <200 mg/Dl ~ Desirable
• 200–239 mg/dL ~ Borderline high
• ≥240 mg/d ~ High
LDL CHOLESTEROL
• <100 mg/dL ~ Optimal
• 100–129 mg/dL ~ Near or above optimal
• 130–159 mg/dL ~ Borderline high
• 160–189 mg/dL ~ High
• ≥190 mg/dL ~ Very high
HDL CHOLESTEROL
• <40 mg/dL ~ Low
• ≥60 mg/dL ~ High
TRIGLYCERIDES
• <150 mg/dL ~ Normal
• 150–199 mg/dL ~ Borderline high
• 200–499 mg/dL ~ High
• ≥500 mg/dL ~ Very high
16. TREATMENT
• Goals of Treatment:
Lower total and LDL CH to reduce the risk of first or recurrent events such as MI,
angina, HF, ischemic stroke, or peripheral arterial disease.
Optimizing TLC and pharmacologic therapy.
Establishing targeted changes and outcomes with consistent reinforcement of goals and
measures at follow-up visits to attain goals are important to reduce barriers for
optimizing TLC (Therapeutic life style changes ~ Non-pharmacological Therapy) and
pharmacologic therapy.
Assessment of risk factors is needed to more clearly define disease risk
17. TREATMENT
Four risk categories modify the goals and modalities of LDL-lowering therapy:
1. Highest risk = Known CHD or CHD risk equivalents; risk for coronary events is at least as
high as for established CHD (ie, >20% per 10 years, or 2% per year).
2. Moderately high risk = 2 or more risk factors in which 10-year risk for CHD is 10% to
20%.
3. Moderate risk = 2 or more risk factors and a 10-year risk of 10% or less.
4. Lowest risk = 0 to 1 risk factor, which is usually associated with a 10-year CHD risk of
less than 10%.
18. NON-PHARMACOLOGIC THERAPY
• Exercise-for 30 min (aerobic exercise- brisk walking, jogging, swimming, cycling)
• Cessation of smoking
• Wight loss
• Control of hypertension
• Dietary therapy
decrease intake of total fat, saturated fat, and cholesterol
Increase protein and soluble fibers diet (reduces total & LDL cholesterol by 5%-20%)
Antioxidants containing diet (to prevent oxidative stress)
Fish oil supplementation (Fat control & cardio protective)
daily of plant sterols (2 to 3 g) reduces LDL by 6% to 15%.
20. PHARMACOLOGIC THERAPY (FIRST LINE)
CLASS DRUGS MECHANISM OF ACTION
HMG-CoA Reductase
inhibitors (IIa, IIb)
Atorvastatin
Simvastatin
Pravastatin
Lovastatin
Fluvastatin
Rosuvastatin
Θ synthesis of cholesterol in liver,
↑ Lipoprotein uptake by hepatocyte
Bile Acid Binding
Resins (IIa, IIb)
Cholesyramine
Colestipol
Colesevelam
Makes complex with cholesterol (from food &
bile) in Gut & excreted
Preventing absorption of cholesterol
Inhibitor of intestinal
absorption of CH
Ezitimibe (IIa, IIb)
It occupies Receptor (NPC 1 L 1) on intestine
responsible for absorption of CH
Cholestryle ester
transfer protein
inhibitors
Torcetrapib
Anacerapib
CETP plays role in transfer of CE one
lipoprotein to another i.e. Blocked by this class
of drugs (under clinical trial)
21. PHARMACOLOGIC THERAPY (SECOND LINE)
CLASS DRUGS MECHANISM OF ACTION
Activator of
Lipoprotein lipase/
Fibrates (IIb, III,IV)
Gemfibrozile
Bezafibrate
Fenofibrate
Ciprofibrate
*Nucleus receptor (PPAR-α) ↑ Expression of
Lipoprotein lipase (endothelium) & ↑ Apo-AI
that facilitate reverse CH transport
Θ atherosclerotic plaque rupture
↓ entry of cholesterol into cells
↓ Plasma Fibrinogen- Θ Thrombogenesis
Inhibitor of VLDL
Secretion & Lypolysis
Niacin/ Nicotinic acid
(IIb, IV)
Θ Lypolysis, ↓ circualating FFA, VLDL, LDL
↑ Size of LDL i.e. less atherogenic
↑ secretion of plasminogen-↓ Plasma
Fibrinogen thus Θ Thrombogenesis
Miscellenious
Gugulipid Θ CH Biosynthesis, ↑ Excretion of CH
Fish Oil
(Omega-3 fatty acid)
Antioxidant Activity
22. TYPE
ELEVATION IN
LIPROTEIN
ELEVATION IN
LIPIDS RISK
TREATMENT
DRUG COMBINATION
TG CH
I CM +++ +/N NO None None
IIa LDL N ++ HIGH
Statines
Resins
niacin, Ezitimibe
Resins ± Ezitimibe, Resins + niacin
Resins + Statines, niacin + Statines
Statines ± Ezitimibe
Resins + niacin + Statines
IIb VLDL & LDL ++ ++ HIGH
Statines, fibrates,
niacin, Ezitimibe
Resins + fibrates
Resins + niacin, niacin + Statines
Resins + niacin + Statines
III
REMNANT OF
VLDL & CM ++ ++ MOD
fibrates, niacin
Ezitimibe
Statins + niacin
Statins + fibrates
IV VLDL +++ +/N MOD fibrates, niacin Niacin + Fibrates
V VLDL & CM ++ +/N NO
None, niacin if
needed
Niacin + Fish oil - if needed
23. TYPES OF HYPERLIPOPROTTEINAEMIA
Resins + Fibrates IIb ↑risk of Cholelethiasis
Resins + Niacin IIa, IIb Acid Neutralising actvity- ↓GI irritation
Resins + Statines IIa
Statin given 4hr prior to Resins- for better absorption
Highly effective to ↓LDL-C
Resins + Niacin +
Statines
IIa, IIb In patient of severely raised LDL-C
Niacin + Statines
Combined-
IIa, IIb
For those having ↑LDL-C & ↓HDL-C
Statines + Ezitimibe IIa Highly absorbed ,↓ses CH synthesis & absorption
Statines + Fibrates any
Highly risk patient having ↑ TG abnormally
Carefully watched for myopathy
24. TREATMENT OF LOW HDL-CHOLESTEROL
• Low HDL cholesterol is a strong independent risk predictor of CHD.
• ATP III redefined low HDL cholesterol as less than 40 mg/dL (<1.03 mmol/L)
• specified no goal for HDL raising.
• In low HDL, the primary target remains LDL reduction.
• but treatment emphasis shifts to weight reduction, increased physical activity, and
smoking cessation. (TLC)
• Drug Therapy: fibrates and niacin
25. TREATMENT OF LOW HDL-CHOLESTEROL
• Low HDL cholesterol is a strong independent risk predictor of CHD.
• ATP III redefined low HDL cholesterol as less than 40 mg/dL (<1.03 mmol/L)
• specified no goal for HDL raising.
• In low HDL, the primary target remains LDL reduction.
• but treatment emphasis shifts to weight reduction, increased physical activity, and
smoking cessation. (TLC)
• Drug Therapy: fibrates and niacin
26. EVALUATION OF THERAPEUTIC OUTCOMES
• PERIODIC measurement of total cholesterol, LDL-C, HDL-C, and triglycerides.
Many patients treated for primary dyslipidemia have no symptoms or clinical
manifestations of a genetic lipid disorder (eg, xanthomas), and monitoring may be
solely laboratory based.
• In patients treated for 20 intervention, symptoms of atherosclerotic CV disease,
such as angina and intermittent claudication, may improve over months to years.
Xanthomas /other external manifestations of dyslipidemia -regress with therapy.
• Obtain lipid measurements in the fasting state to minimize interference from CM.
Monitoring is needed every few months during dosage titration.
Once the patient is stable, monitoring at intervals of 6 months to 1 year is sufficient.
27. EVALUATION OF THERAPEUTIC OUTCOMES
• Patients on BAR therapy should have a fasting panel checked every 4 to 8 weeks until a
stable dose is reached;
check triglycerides at a stable dose to ensure they have not increased.
• Niacin requires baseline tests of liver function (alanine aminotransferase), uric acid,
and glucose.
Repeat tests are appropriate at doses of 1,000 to 1,500 mg/day.
Symptoms of myopathy or diabetes should be investigated and may require creatine
kinase or glucose determinations.
Patients with diabetes may require more frequent monitoring.
28. EVALUATION OF THERAPEUTIC OUTCOMES
• Patients receiving statins should have a fasting lipid panel 4 to 8 weeks after the initial
dose or dose changes.
Obtain liver function tests at baseline and periodically thereafter.
Some experts believe that monitoring for hepatotoxicity and myopathy should be
triggered by symptoms.
• For patients with multiple risk factors and established CHD, evaluate for progress in
managing other risk factors such as BP control, smoking cessation, exercise and weight
control, and glycemic control (if diabetic).
• Evaluation of dietary therapy & patient adherence to dietary recommendations.
