Dr.Sarma

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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 : +91-98940 60593

subha-rani@eth.net

Dr.Sarma

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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

Sedentary Life Style

Less perfect Genetic make-up

Diets rich in Saturated Fat, Chol

Excess body weight/ Obesity

Lipid abnormalities

Atherosclerotic vascular disease

CHD, CVD, PVD

tHcy

ROS

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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

TG, EC

Phospholipids Free Cholesterol

(Hydrophilic)

Apoproteins A, B, C, E, (a) (Amphipathic)

Lipids or Fats (Hydrophobic)Size < RBC

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ECTG

Lipid Transport

Apoprotein boat

Apo A = HDL Apo B100+C+E = VLDL, IDL

Apo B100 = LDL Apo B48+C+A+E = Chylomicrons

Solubilizes

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Composition

TG 95 %

EC 5%

TG 80 %

EC 20%

Chylomicrons VLDL

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Composition

TG 15 %

EC 85%

TG 5 %

EC 95%

LDL HDL

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Particle size & Density

Chylomicrons

<< 1.006

VLDL

< 1.006

IDL

< 1.019

LDL

< 1.063

Small LDL

< 1.085

HDL

< 1.210

Atherogenicity is a function of the density

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Lipoproteins

Lipoprotein TG Chol. Apoprotein

Chylomicrons 95 5 B48+C+E+A

VLDL 80 20 B100+C+E

IDL 30 70 B100+E

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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LIVER

Reverse Cholesterol Transport

Vascular Endothelial Cell

Free Chol.

L CAT Enzyme

UECEC

HDL

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Enzymes

1. 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

2. 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..

3. 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-

4. 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

Oxidized LDL, IDL

Freely enters the vessel wall

Scavenger pathway

Endothelium Macrophages

Foam Cells Cytokines, GF

Atherosclerosis

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Lipid Peroxidation

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Primary HyperlipidaemiasFamilial 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 StrategyLipid Profile, Risk Assessment

LDL > 100 Look For Sec. Causes

Treat the cause, if found

Treatment

Sec. PreventionPrimary Prevention

High Risk Low Risk

LDL > 130

LDL >160

CHD +

NO CHD

< 2 RF 2 or > RF

LDL > 100

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Treatment StrategyFasting TG Level TG < 150

↑Fasting TG LevelNormal

< 2 RF

TG >150, No CHD

TG > 150, CHD +

TG > 500, CHD +/-

Diet Modif.

Diet + Fibrate

2 or > RF

Diet + Fibrate + Niasyn

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

LIPIDS ESTIMATED

TOTAL CHOLESTEROL TRIGLICERIDES

HDL LDL VLDL Chylomicrons VLDL

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Lipid Profile Report

LIPID TYPE LIPOPROTEIN Normal Remarks

TC = 250 HDL = 50 > 45 N

LDL = 170 < 130 Abnormal

VLDL = 30 < 60 N

TG = 150 VLDL = 135 < 150 N

Chylomicron=15 < 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 – (50+30)

= 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

1. Cigarette smoking

2. Hypertension (BP 140/90 mmHg or on antihypertensive medication)

3. Diabetes Mellitus

4. Low HDL cholesterol (< 40 mg/dl)†

5. Family history of premature CHD• CHD in first degree ♂ relative of < 55 years• CHD in first degree ♀ relative < 65 years

6. Age (men 45 years; women 55 years)† HDL cholesterol 60 mg/dL counts as a “negative” risk factor;.

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34Risk Factors Ranking in the PROCAM Study

Risk factor Relative risk P Value

Smoking 2.30.001

LDL cholesterol (mg/dl)130-160 1.90.01>160 4.30.001

Hypertension 1.80.001

HDL cholesterol (mg/dl)55 - 45 1.70.01< 45 2.70.001

Triglycerides (mg/dl)105- 167 1.60.01>167 2.60.001

Fasting blood glucose (mg%)110-126 1.40.05> 126 1.90.01

Family history of MI 1.40.05

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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%

D+E 47.35%

IHJ, 2000, 52: 173-177Am J Med, 1998, vol 105(1A), 48S-56S

The Triad

↑LDL

↓HDL

↑TG

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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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• Modification of Lipid and Lipoprotein Classification

• LDL cholesterol < 100 mg/dl—optimal• HDL cholesterol < 40 mg/dl

• Categorical risk factor• Raised from < 35 mg/dl

• Lower triglyceride classification cut points• More attention to moderate elevations• > 150 mg itself is indication for Rx.

New Features of ATP III cont..

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• LDL cholesterol is the primary target for therapy

• Non HDL Cholesterol is the secondary target for therapy

Non HDLc = (TC – HDLc)

= (LDLc + VLDLc)

New Features of ATP III cont..

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New Features of ATP III (continued)

New Recommendation for Screening/Detection

1. Complete lipoprotein profile preferred• Fasting (12 h) TC, LDL, HDL, TG

2. Secondary option• Non-fasting total cholesterol and HDL• If TC. is 200 mg/dL or HDL < 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

< 2 RF

<160 >160 >190

No CHD

2 or more RF

<130 >130 >160

CHD Present <100 >100 >130

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Triglycerides

TG Level Classification Treatment

< 150 mg% Normal TG No Rx.

150 to 200 mg% Borderline high Diet alone

201 to 500 mg% High Diet + drugs

> 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

1. HMG¢ CoA Reductase Inhibitors

2. Bile Acid binding Resins

3. Nicotinic Acid

4. Fibric Acid derivatives

5. Probucol

¢ HMG is Hydroxy Methyl Glutaryl

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Therapeutic Lifestyle Changes - TLC

Nutrient Recommended Intake• Saturated fat < 7% of calories• PUFA fat Up to 10% of calories• MUFA fat Up to 20% of calories• Total fat 25–35% of calories• Carbohydrate 50–60% of calories• Fiber 20–30 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 18–55% & TG 7–30%

• Raise HDL-C 5–15%, No action on Lp(a)

• Major side effects – (< 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 20–80 mgPravastatin 20–40 mgSimvastatin 20–80 mgFluvastatin 20–80 mgAtorvastatin 10–80 mgCerivastatin 0.4–0.8 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

Demonstrated Therapeutic Benefits

• Reduce major coronary events

• Reduce CHD mortality

Act by interfering with entero-hepatic

circulation of bile acids and Cholesterol

sequestration

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Bile Acid SequestrantsMajor actions

• Reduce LDL-C 15–30%• Raise HDL-C 3–5%• May increase TG

Side effects• GI distress/constipation/nausea• Decreased absorption of other drugs

Contra indications• Dys-betalipoproteinemia,• Biliary Obstruction• Raised TG (especially >400 mg/dL)

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Bile Acid Sequestrants

Drug Dose Range

Cholestyramine 4–16 g

Colestipol 5–20 g

Colesevelam 2.6–3.8 g

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Nicotinic AcidMajor Actions– Lowers TG 20–50%, – VLDL by 20-35%– Raises HDL-C 15–35%– Only agent – lowering Lp(a) by 25%

Side effects Flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity, pruritus tachycardia and atrial arrythmiasContra indications Liver disease, severe gout, peptic ulcer

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Nicotinic Acid

Drug Form Dose Range

Immediate release 1.5–3 g

(crystalline)

Extended release 1–2 g

Sustained release 1–2 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 5–20% (with normal TG)– May raise LDL-C (with high TG)– Lower TG 20–50%, ↓VLDL synthesis– Raise HDL-C 10–20%– 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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ProbucolProbucol (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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What’s 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

Gordon, Castelli et al. Am J Med 1977; 62: 707–714

0

50

100

150

200

Rat

e/10

00

<25 25–34 35–44 45–54 55–64 65–74 75+

HDL-C (mg/dl)

Women

Men

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Relative risks of MI

3.21

3.78

1.00

2.41 Low HDL cholesterol<47 mg/dl

High HDL cholesterol47 mg/dl

Low total cholesterol<212 mg/dl

High total cholesterol212 mg/dl

Stampfer, Sacks et al. N Engl J Med 1991; 325: 373–381

The Physicians Health Study

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HDL-C vs LDL-C as a predictor of CHD risk

*Men aged 50–70

Gordon, Castelli et al. Am J Med 1977; 62: 707–714

100 mg/dl 160 mg/dl 220 mg/dl0

0.5

1

1.5

2

2.5

3

Risk of CAD over 4years of follow-up*

LDL-C

85 mg/dl

65 mg/dl

45 mg/dl

25 mg/dl

CHD RR

HDL-C

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Low HDL Cholesterol (< 40)

• Elevated triglycerides

• Overweight / Obesity, Physical inactivity

• Type 2 diabetes

• Cigarette smoking

• Very high carbohydrate intake (> 60% cal.)

• Certain drugs (beta-blockers, anabolic steroids, progestational agents)

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• 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)

Management of Low HDLc

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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 %, > 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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• 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

Association of Lp(a) to CAD

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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 Jacob’s Disease– Tsutsugamushi Fever– Criggler Nazzar Syndrome– South American equine encephalitis and – Many and much more

BUT

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The AlmightyWill 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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Sarvae Jana Sukhino BhavantuBest Wishes for a

Happy New Year