Dr. R.V.S.N.Sarma, M.D., M.Sc (Canada)

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Dr. R.V.S.N.Sarma, M.D., M.Sc (Canada)

• Consultant Physician
• and Chest Specialist
• 1, Jayanagar, Tiruvallur,
• Chennai -602 001

(04116) 260593, 263665 Mobile [phone]
60593 subha-rani_at_eth.net
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Best Wishes to You All
From IMA Tamil Nadu
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LIPIDS

• An overview of
• Normal and Abnormal Lipids

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Lipid Abnormalities
Diets rich in Saturated Fat, Chol
Sedentary Life Style
Excess body weight/ Obesity
ROS
Less perfect Genetic make-up
Lipid abnormalities
Atherosclerotic vascular disease
CHD, CVD, PVD
tHcy
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AVD Clinical Manifestations
Organ Condition Impairment Clinical Presentation
Heart Coronary Heart Disease (CHD) Ischemia Infarction Angina Pectoris Myocardial Infarction
Brain Cerebro vascular Disease (CVD) Ischemia Infarction Transient Ischemia attack Stroke
Kidney Reno vascular Disease (RVD) Ischemia Infarction Reno vascular hypertension Renal impairment Renal Failure
Leg Muscles Peripheral Vascular Disease (PVD) Ischemia Infarction Intermittent Claudication Gangrene
For every thing the common denominator is ED
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Lipids and Lipoproteins

• Lipids or Fats in our body are mainly
• The non polar, hydrophobic, inner core of
• Triglycerides (TG)
• Cholesterol Esters (EC)
• The polar, surface monolayer, hydrophilic
• Phospholipids (PL) and Free Cholesterol (C)
• Apoproteins are the outer coat - amphipathic

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Lipoprotein
Lipids or Fats (Hydrophobic)
Size lt RBC
TG, EC
Apoproteins A, B, C, E, (a) (Amphipathic)
Phospholipids Free Cholesterol (Hydrophilic)
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Lipid Transport
Solubilizes
Apo A HDL Apo B100CE VLDL, IDL Apo B100
LDL Apo B48CAE Chylomicrons
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Composition
TG 95
TG 80
EC 20
EC 5
Chylomicrons
VLDL
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Composition
TG 15
TG 5
EC 95
EC 85
LDL
HDL
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Particle size Density
Atherogenicity is a function of the density
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Lipoproteins
Lipoprotein TG Chol. Apoprotein
Chylomicrons 95 5 B48CEA
VLDL 80 20 B100CE
IDL 30 70 B100E
LDL 15 85 B100
Small LDL 10 90 B100
HDL 5 95 AI, AII
Lp(a) 10 90 B100(a)
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Lipoprotein Metabolism

• Exogenous
• Transport of dietary fats TG to Adipose tissue,
  Muscle and Cholesterol to Liver as Chylomicrons
• Endogenous
• Transport of TG and CE from Liver to the
  peripheral tissues like muscle, adipose tissues
  and vascular endothelium via VLDL,IDL, LDL
• Reverse Cholesterol transport HDL Path
• from the vessels and periphery to liver
  

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Reverse Cholesterol Transport
UEC
L CAT Enzyme
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Enzymes

• Lipo Protein Lipase (LPL)
• Synthesized in Adipose and Muscle tissues
• Essential for TG metabol FFA and Glycerol
• Insulin activates LPL,- CII apo binds to LPL
• Hepatic TG Lipase (HTGL)
• Removes TG from VLDL, IDL LDL
• Clears the Cholesterol remnants into liver
• Converts HDL2 to HDL3 in the liver

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Enzymes contd..

• Lecithin Chol Acyl Transferase (LCAT)
• Secreted into plasma by the liver
• Binds to HDL and transfers linoleate from
  lecithin to free Chol and converts it into EC-
• Cholesterol Ester Transfer Protein (CETP)
• Secreted into plasma from liver
• Transfers EC from HDL to VLDL
• Converts LDL to small Dense LDL

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Lipid Peroxidation
LDL, IDL
Not normally taken up by the vessel wall
ROS Free radicals and Pro-oxidants
Freely enters the vessel wall
Oxidized LDL, IDL
Macrophages
Endothelium
Scavenger pathway
Foam Cells
Cytokines, GF
Atherosclerosis
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Lipid Peroxidation
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(No Transcript)
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Primary Hyperlipidaemias
Familial Hyper Cholesterolemia II a ?LDL
Familial defect in apo B 100 II a ?LDL
Polygenic Hyper Cholesterolemia II a ?LDL
Familial Hyper Triglyceridemia IV ?VLDL
Familial LPL deficiency I, V ?Chylo
Familial apo CII deficiency I, V ?Chylo
Combined Hyperlipedemia II b ?VLDL,?LDL
Dys-Beta lipoproteinemia III ?VLDL,?IDL
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Secondary Hyperlipidemia
Cholesterol TG
Nephrotic syndrome. Obesity
Hypothyroidism Diabetes
Obstr. liver disease Uraemia
Anorexia nervosa Alcoholism, Smoking
Acute Int. Porphyria Oral contraceptives
Progestogens Beta blockers
Thiazides Pregnancy
Anabolic steroids Steroids, Thiazides
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Clinical Photos
Tuberous xanthoma. Flat-topped,
yellow, firm tumor
Xanthelasma. Multiple, longitudinal,
creamy-orange, slightly elevated papules on
eyelids .
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Clinical Photos
Tendinous xanthomas. Large sub-cutaneous tumors
adherent to the Achilles tendons.
Papular eruptive xanthomas. Multiple, discrete,
red-to-yellow confluent papules
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Evaluation

1. History of eruptive xanthomas, Abd. pain
2. H/o wt. gain, DM, estrogens, Alcohol, Ex.
3. Fasting Lipid profile (TC, LDL, HDL, TG)
4. OGTT, TSH, Liver Renal Function tests
5. CHD assessment by ECG, TMT, Angio
6. Risk factor assessment, Family H/o P.CHD

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Treatment Strategy
Lipid Profile, Risk Assessment
LDL gt 100
Look For Sec. Causes Treat the cause, if found
Treatment
NO CHD
CHD
Primary Prevention
Sec. Prevention
LDL gt 130
lt 2 RF
2 or gt RF
High Risk
Low Risk
LDL gt 100
LDL gt160
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Treatment Strategy
Fasting TG Level
TG lt 150
Normal
?Fasting TG Level
lt 2 RF
Diet Modif.
TG gt150, No CHD
2 or gt RF
Diet Fibrate
TG gt 150, CHD
Diet Fibrate Niasyn
TG gt 500, CHD /-
Diet Fibrate Statin
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Clinical Action

• Presence of secondary causes of Hyperlipidemia
• Order for full lipid profile (LP) HT also
• Presence of Hyperlipidemia increased TG or EC
• Investigate for all secondary causes
• For all above 20 years once in every 5 years LP
• For those above 45 yrs once in 2 years
• For those with already known lipid abnormality
  follow-up every 3-6 months

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Lipid Profile Report
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Lipid Profile Report
LIPID TYPE LIPOPROTEIN Normal Remarks
TC 250 HDL 50 gt 45 N
LDL 170 lt 130 Abnormal
VLDL 30 lt 60 N
TG 150 VLDL 135 lt 150 N
Chylomicron15 lt 30 N
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LDLc Calculation

• LDLc TC (HDLc TG/5)
• e.g. if TC 250, HDLc 50, TG 150
• LDLc 250 (50 150/5)
• 250 (5030)
• 250 (80)
• LDLc 170

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Adult Treatment Panel III (ATP III) Guidelines
-2002

• National Cholesterol
• Education Program - NCEP

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Categories of Risk Factors

1. Major, independent risk factors
2. Life-habit risk factors
3. Emerging risk factors
4. CHD risk equivalents

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Major Risk Factors for CHD - LDLc

• Cigarette smoking
• Hypertension (BP ?140/90 mmHg or on
  antihypertensive medication)
• Diabetes Mellitus
• Low HDL cholesterol (lt 40 mg/dl)
• Family history of premature CHD
• CHD in first degree ? relative of lt 55 years
• CHD in first degree ? relative lt 65 years
• Age (men ? 45 years women ? 55 years)

HDL cholesterol ? 60 mg/dL counts as a
negative risk factor.
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Risk Factors Ranking in the PROCAM Study

• Risk factor
  Relative risk P Value

Smoking 2.3 0.001 LDL cholesterol
(mg/dl) 130-160 1.9 0.01 gt160 4.3 0.001 Hyperten
sion 1.8 0.001 HDL cholesterol (mg/dl) 55 -
45 1.7 0.01 lt 45 2.7 0.001 Triglycerides
(mg/dl) 105- 167 1.6 0.01 gt167 2.6 0.001 Fasting
blood glucose (mg) 110-126 1.4 0.05 gt
126 1.9 0.01 Family history of MI 1.4 0.05
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Dyslipidemia in Indiansuncomplicated non
diabetic hypertensives(3182) vs controls (4131)

• A. Hypercholesterolemia 32.90
• B. Low HDL 21.35
• C. Isolated elevated triglycerides 10.45
• D. Abnormal TC/HDL ratio 32.00
• E. Abnormal TC/HDL ratio with elevated Tg 15.35
• DE 47.35

The Triad
IHJ, 2000, 52 173-177
Am J Med, 1998, vol 105(1A), 48S-56S
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Life-Habit Risk Factors

1. Obesity (BMI ? 30)
2. Physical inactivity
3. Atherogenic diet

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Emerging Risk Factors

1. Lipoprotein (a)
2. Homocysteine
3. Prothrombotic factors
4. Pro-inflammatory factors
5. Impaired fasting glucose 110- 126
6. Sub-clinical atherosclerosis

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CHD Risk Equivalents

• Diabetes Mellitus
• Reno-vascular Disease
• Chronic Nephropathy
• Peripheral Vascular Disease
• Established CVA
• All forms of AVD

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New Features of ATP III

• Focus on Multiple Risk Factors
• Diabetes CHD risk equivalent
• Framingham projections of 10-year CHD risk
• Identify patients with multiple risk
  factors for more intensive treatment
• Multiple metabolic risk factors (metabolic / X
  syndrome, IR)

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New Features of ATP III cont..

• Modification of Lipid and Lipoprotein
  Classification
• LDL cholesterol lt 100 mg/dloptimal
• HDL cholesterol lt 40 mg/dl
• Categorical risk factor
• Raised from lt 35 mg/dl
• Lower triglyceride classification cut points
• More attention to moderate elevations
• gt 150 mg itself is indication for Rx.

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New Features of ATP III cont..

• LDL cholesterol is the primary target for therapy
• Non HDL Cholesterol is the secondary target for
  therapy
• Non HDLc (TC HDLc)
• (LDLc VLDLc)

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New Features of ATP III (continued)

• New Recommendation for Screening/Detection
• Complete lipoprotein profile preferred
• Fasting (12 h) TC, LDL, HDL, TG
• Secondary option
• Non-fasting total cholesterol and HDL
• If TC. is ?200 mg/dL or HDL lt 40,
  then proceed to do a full Lipid Profile

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Approach to Therapy

• Education on diet and exercise
• Increase physical activity
• Decrease body weight
• Employ drug therapy

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Treatment Plan - LDLc
Clinical Status Goal Diet Drugs
No CHD lt 2 RF lt160 gt160 gt190
No CHD 2 or more RF lt130 gt130 gt160
CHD Present lt100 gt100 gt130
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Triglycerides
TG Level Classification Treatment
lt 150 mg Normal TG No Rx.
150 to 200 mg Borderline high Diet alone
201 to 500 mg High Diet drugs
gt 500 mg Very high Diet Intensive Rx
NCEP 2002 Guidelines by expert panel on TG
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Treatment Options

• Diet Two step approach
• Drug therapy
• HMG CoA Reductase Inhibitors
• Bile Acid binding Resins
• Nicotinic Acid
• Fibric Acid derivatives
• Probucol

HMG is Hydroxy Methyl Glutaryl
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Therapeutic Lifestyle Changes - TLC

• Nutrient Recommended Intake
• Saturated fat lt 7 of calories
• PUFA fat Up to 10 of calories
• MUFA fat Up to 20 of calories
• Total fat 2535 of calories
• Carbohydrate 5060 of calories
• Fiber 2030 grams per day
• Protein Approx. 15 of calories
• Cholesterol Less than 200 mg/day

DIETARY THERAPY
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ATP III Guidelines
Drug Therapy
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HMG CoA Reductase Inhibitors (Statins)

• Chol. synthesis is ?by enzyme inhibition
• Reduce LDL-C 1855 TG 730
• Raise HDL-C 515, No action on Lp(a)
• Major side effects (lt 5)
• 1. Myopathy 2. Increased liver enzymes
• Contraindications
• 1. Absolute liver disease
• 2. Relative use with certain drugs

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HMG CoA Reductase Inhibitors (Statins)

• Statin Dose Range
• Lovastatin 2080 mg
• Pravastatin 2040 mg
• Simvastatin 2080 mg
• Fluvastatin 2080 mg
• Atorvastatin 1080 mg
• Cerivastatin 0.40.8 mg

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HMG CoA Reductase Inhibitors (Statins)
(continued)

• Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality
• Reduce coronary procedures
• (PTCA/CABG)
• Reduce stroke
• Reduce total mortality

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Bile Acid Sequestrants
Act by interfering with entero-hepatic circulation
of bile acids and Cholesterol sequestration

• Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality

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Bile Acid Sequestrants

• Major actions
• Reduce LDL-C 1530
• Raise HDL-C 35
• May increase TG
• Side effects
• GI distress/constipation/nausea
• Decreased absorption of other drugs
• Contra indications
• Dys-betalipoproteinemia,
• Biliary Obstruction
• Raised TG (especially gt400 mg/dL)

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Bile Acid Sequestrants

• Drug Dose Range
• Cholestyramine 416 g
• Colestipol 520 g
• Colesevelam 2.63.8 g

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Nicotinic Acid

• Major Actions
• Lowers TG 2050,
• VLDL by 20-35
• Raises HDL-C 1535
• Only agent lowering Lp(a) by 25
• Side effects
• Flushing, hyperglycemia, hyperuricemia, upper GI
  distress, hepatotoxicity, pruritus tachycardia
  and atrial arrythmias
• Contra indications
• Liver disease, severe gout, peptic ulcer

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Nicotinic Acid

• Drug Form Dose Range
• Immediate release 1.53 g
• (crystalline)
• Extended release 12 g
• Sustained release 12 g

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Nicotinic Acid

• Demonstrated therapeutic benefits
• Reduces major coronary events
• Possible reduction in total mortality
• Poor side effect profile is the limitation
• Can be combined with statins, fibric
• acid derivatives

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Fibric Acid Derivatives

• Major actions
• Lower LDL-C 520 (with normal TG)
• May raise LDL-C (with high TG)
• Lower TG 2050, ?VLDL synthesis
• Raise HDL-C 1020
• Act by ?LPL activity and TG hydrolysis
• Side effects
• Dyspepsia, gallstones, myopathy, Abn. LFT
• Contraindications
• Severe renal or hepatic/ biliary disease

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Fibric Acid Derivatives

• Drug Dose
• Gemfibrozil 600 mg BID
• Fenofibrate 200 mg QD
• Clofibrate 1000 mg BID

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Fibric Acid Derivatives

• Demonstrated Therapeutic Benefits
• Reduce progression of
• coronary lesions
• Reduce major coronary events

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Probucol

• Probucol (Lorelco) 500mg b.i.d with food
• Third line drug erratic effect on LDL
  decrease of HDL
• Lowers Cholesterol and the only drug which
  regresses xanthomas
• It is an antioxidant of LDL
• Diarrohea, flatulence, nausea, increases QTc
• Can be combined with bile acid sequestrating
  resins

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Summary of Drug choice

• LDLc is more Hypercholesterolemia alone
• Statins 1st line Simvastatin Atorvastatin
• Statins Anion resin (Questron) 2nd line
• Or Statins nicotinc acid 2nd line
• Probucol 3rd line specially for xanthomas
• But not Statins gemfibrozil
• TG alone is elevated Hyper-triglyceridemia
• Gemfibrozil 1st line
• Nicotinic acid with or without Gemfibrozil 2nd
  line
• For mixed combination- Statin Nicotinic acid

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Whats in a name ?

• Statins
• Atorvastatin Storvas, TG-tor, Avastin
  Simvastatin Sim, Simvotin
• Bile acid sequestering resins
• Cholysteramine Questron
• Colistipal Colestid
• Nicotinic Acid Niasyn
• Fibric acid -Gemfibrozil Lopid, Lipizyl
• Fenfibrate - Lipicard
• Probucol Lorelco

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Coronary heart disease and HDL-CFramingham Heart
Study
200
150
Rate/1000
100
Women
50
Men
0
lt25
2534
3544
4554
5564
6574
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HDL-C (mg/dl)
Gordon, Castelli et al. Am J Med 1977 62 707714
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Relative risks of MI
The Physicians Health Study
3.78
3.21
Low HDL cholesterol lt47 mg/dl
2.41
1.00
High HDL cholesterol ?47 mg/dl
Low total cholesterol lt212 mg/dl
High total cholesterol ?212 mg/dl
Stampfer, Sacks et al. N Engl J Med 1991 325
373381
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HDL-C vs LDL-C as a predictor of CHD risk
CHD RR
Risk of CAD over 4 years of follow-up
3
2.5
HDL-C
2
1.5
25 mg/dl
45 mg/dl
1
65 mg/dl
0.5
85 mg/dl
0
100 mg/dl
160 mg/dl
220 mg/dl
LDL-C
Men aged 5070
Gordon, Castelli et al. Am J Med 1977 62 707714
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Low HDL Cholesterol (lt 40)

• Elevated triglycerides
• Overweight / Obesity, Physical inactivity
• Type 2 diabetes
• Cigarette smoking
• Very high carbohydrate intake (gt 60 cal.)
• Certain drugs (beta-blockers, anabolic steroids,
  progestational agents)

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Management of Low HDLc

• LDL cholesterol is primary target of therapy
• Weight reduction and increased physical activity
  (if the metabolic syndrome is present)
• Non-HDL cholesterol is secondary target of
  therapy (if triglycerides ?200 mg/dL)
• Consider nicotinic acid or fibrates (for
  patients with CHD or CHD risk equivalents)

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Homocystine

• Normal value is up to 15 µ mols./l
• Folic acid, Vitamin B6 and B12 are essential for
  the normal transulfuration and remethylation
  cycles
• Excess of homocystine generates oxidative stress
  on the cell membranes. DNA and protein
  denaturation through ROS formation
• Folic acid 5 mg/ day Vit. B6 and B12 are to be
  given on regular basis

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Lp (a) or Little a

• Similar to LDL molecule
• A single apo-A is attached by a disulfide
  bond to apo-B 100
• Primary determinant is genetic
• Normal value 20 mg , gt 30 high risk
• It competes with plasminogen because of its
  structural similarity and so interferes with
  plasmin synthesis and thrombolytic pathway
• Nicotinic acid, ? Benzafibrate, Estrogens ?it

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Association of Lp(a) to CAD

• Meta analysis of 27 prospective studies, 5436 CHD
  cases, F/u of 10 yrs
• People with Lp(a) levels in the top third of
  baseline measurement are at about 70 increased
  risk of CHD compared with those in the bottom
  third.
• Circulation, 2000, 102 1082-1085
• Serum Lp(a) is an independent risk factor for CAD
  in NIDDM patients in south India
• Diabetes care, 1998, 21, 1819-1823

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Insulin Resistance

• Metabolic syndrome
• Multi system disorder
• Predisposes to DM CVD
• Contributors to IR
• 1. Genetic 2. Obesity abdominal
• 3. Physical inactivity 4. Advancing age

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Insulin Resistance

• Atherogenic dyslipidemia
• ? In VLDL, ? in small LDL, ? in HDL
• Prothrombotic state
• ? In fibrinogen levels
• ? In plasminogen activator inhibitor
• Various platelet abnormalities
• G.T. Abnormalities IGT, hyper glycemia
• Hypertension

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Evidence for Insulin Resistance

• Abdominal obesity
• B.P High normal or Mild HT
• TG high normal ?250
• Lowered HDL ? 40 for men, ? 50 women
• Boarder line LDL - 130- 155 mg
• IGT -- FPG 110- 126 mg
• Having Diabetes is equivalent to having IHD

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The Research
ADMIT Arterial disease multiple intervention trial (Niacin, Anti-oxidants, vitamins)
CHAOS Cambridge heart anti-oxidant study
MRC/BHF HPS MRC/BHF heart protection study (anti-oxidants)
SU.VI.MAX Supplementation en Vitamines et Mineraux Antioxydants
CELL Cost Effectiveness of Lipid Lowering (pravastatin)
CIS Coronary Intervention Study (simvastatin)
HHS Helsinki Heart Study (Gemfibrozil for TG)
SSSS (4S) Scandinavian Simvastatin Survival Study (Land mark trial
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The Future Research

• We do not have yet any drug which increases the
  HDL
• We do not know the precise role of Lp(a) and how
  to reduce it.
• Small LDL needs further evaluation
• RCTs to prove that the anti-oxidants have a real
  role to play both in treatment and in prevention
  of AVD

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The Almighty

• May pardon and grant me heaven
• Even if I don't know a single letter about
• Crutz Feld Jacobs Disease
• Tsutsugamushi Fever
• Criggler Nazzar Syndrome
• South American equine encephalitis and
• Many and much more
• BUT

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The Almighty

• Will drag me to hell and will not pardon my
• Ignorance of even the minute details common
  diseases like DM, HT, IHD, Dyslipedimias etc.,
• Indifference to apply current knowledge
• Negligence in screening for Lipid abnormalities
• Despondency about preventing CHD, DM, IR
• Inadequacy in maintaining my patients as
  normo-tensive, normo-glycemic, and normo-lipemic
  as possible
• (This is applicable to all common diseases)

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Do You Who I am ?

• I am the primary care physician
• on whom my patients bestow all trust

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Thanks Everyone
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Best Wishes for a Happy New Year
Sarvae Jana Sukhino Bhavantu