dyslipidemia update by dr sarma

8/12/2019 Dyslipidemia Update by Dr Sarma

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O ALMIGHTY

Tallee ninnu dalanchi pustakamu

chaetan boonitin neevu naa

ullambanduna nilchi jrumbhanamugaan

uktul su sabdambul

sobhillan balkumu naadu vaakkunan

sampreetin, Jaganmohinee

pullaabjaakshee Saraswatee Bhagavatee

poornaendu bimbaanana


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O! Almighty, the Goddess of Wisdom!

We start this learning process, keeping

YOU in our inner hearts, please shower

Your kind blessings on all of us and ensure

What ever we speak is eloquent

What ever we discuss is pertinent

What ever we learn is relevant.

May we be blessed with the best wisdom !

O! ALMIGHTY


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Dr.Sarma RVSN, M.D., M.Sc (Canada)Consultant in Medicine and Chest,

# 3, Jayanagar, Tiruvallur 602 001

98940 60593, 2766 0593

Visit us at : www.drsarma.in

Dyslipidemias-Practice Approach


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CD ROM Available

The contents of my todays presentations

are made available in a CD-ROM format

This CD, in addition, contains my talks on

Asthma, COPD, Hypertension, ECG, CAD

Dyslipidemias, Diabetes, Osteoporosis


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The Almighty

Pardons and Grants 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 rarer topicsBUT .


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The Almighty

Will drag me to hell and will not pardon

My ignorance of even the minute details of HT, DM

My indifference to apply the current knowledge

My negligence in screening for Lipids, DM, HT, LVH

My despondency about preventing TOD and ACS

My inadequacy in maintaining my patients

Normotensive, Euglycemic, Eulipidemic

(This is applicable to all common diseases)


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National Cholesterol

Education Program -NCEP

Adult Treatment Panel III(ATP III) Guidelines -2002

Updated October 2004


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The Good, Bad, Ugly and Deadly


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Two Types of Lipids

LIPIDS IN BLOOD

TOTAL CHOLESTEROL TRIGLYCERIDES (TG)

GOOD CHOLESTEROL

HDL 1 and HDL 2

BAD CHOLESTEROL

LDL, VLDL (TG), Lp(a)


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Lipoprotein

TG, EC

Phospholipids

Free Cholesterol

(Hydrophilic)

Apoproteins A,

B, C, E, (a)

(Amphiphatic)

Lipids or Fats

(Hydrophobic)Size < RBC


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Good, Bad, Ugly & Deadly

CTG

B 100 + E +C

CTG

B 100

CT

GA I, A II

HDL LDL

VLDL

CTG

B 100+ (a)

Lp(a)

TG

GOOD BAD

UGLY DEADLY


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All are the terrorists !!

Apolipoprotein B

Non-HDL-CMeasurements

TG-rich lipoproteins

VLDL VLDLR IDL LDL SDL

Highly atherogenic


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Particle size & Density

Chylomicrons


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LIPIDS ESTIMATED

TOTAL CHOLESTEROL (TC) TRIGLYCERIDES (TG)

HDLc LDLc VLDLc Chylomicrons VLDL

Lipid Profile Report

PP Fasting


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Normal Lipid Profile

Total Cholesterol < 200

TG Ugly Lipid < 150

Bad Cholesterols LDL < 100

HDL Good cholesterol > 50

VLDL is Ugly TG 5 < 30

Lp(a) Deadly cholesterol < 20


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How to interpret Lipid Profile Report?

A. Total Cholesterol

HDL Cholesterol (Soldiers) - Good

Non HDL Cholesterol(Culprits)LDL CholesterolBad fellows

Lipoprotein(a)Deadly fellows

VLDL Cholesterol (1/5 of TG)- Ugly

B. Triglycerides 150

100150

50

200

20

30

Normal Lipid Profile


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Interpret this Lipid Profile Report



Non HDL Cholesterol(Culprits)

LDL CholesterolBad fellows




140

190

50

240

20

30

Hyper cholesterolimia LDL, HDL, TG, Lp(a) - N


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70150

50

200

20

60

Hyper triglyceridemia TG,HDL, LDL, Lp(a) - N



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85135

25

160

20

30

Low HDL :HDL,LDL, TG, Lp(a) - N



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75155

45

200

50

30

High Lipoprotein(a) :Lp(a),HDL, LDL, TG - N



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95175

25

200

20

60

High Lipoprotein(a) :HDL,TG, LDL, Lp(a) - N



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Non HDL Cholesterol(Culprits)

LDL CholesterolBad fellows




120

210

50

260

40

50

Combined Dyslipidemia : TCLDLTG Lp(a)


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Dyslipidemic Triad

A. Isolated High LDL 32.90%

B. Isolated low HDL 21.35%

C. Isolated high TG 10.45%

IHJ, 2000, 52: 173-177

Am J Med, 1998, vol 105(1A), 48S-56S

LDL

HDL

TG

The Triad


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Indian Dyslipidemic Triad

IHJ, 2000, 52: 173-177

Am J Med, 1998, vol 105(1A), 48S-56S

Lp(a)

HDL

TG

The Indian Triad


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Indian Dyslipidemia

Low HDL 39.2%

High TG 32.5%

Lp(a) excess 28.6%

High LDL 10.8%

Normal Lipids 23.5%

Am J C 2001;88(suppl) 9N-13N; 22N


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Look at the risks

Low HDL + High LDL +

LP(a) excess > 30 mg% +

LP(a) excess > 30 mg% + LDL high ++

LP(a) excess > 30 mg% + low HDL +++

LP(a) excess > 30 mg% + Incr. tHCy ++++

LP(a) excess + Incr. tHCy + low HDL +++++

Circulating lipidsare one aspects Tissue lipidcontent is more important

J. Atherosclerosis : Hopkins PN, 199717, 2792


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Intestinal Cholesterol Absorption

Bays H et al. Expert Opin Pharmacother 2003;4:779-790.

Intestinal

epithelial cell

Biliary

cholesterol

Dietary

cholesterol

Luminal

cholesterol

Micellar

cholesterol

Bile

acid

Cholesteryl esters

Freecholesterol

excretion

uptake

ACAT

ABCG5ABCG8

(esterification)

MTP

CM

Throughlymphatic

system to

the liver


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Lymph Enterocyte IntestinalLumen

Cholesterol Absorption

Cholesterol

NPC1L1

CholesterylEster ABCG5/G8

ACAT

Ezetimibe

Avasimibe


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Triglyceride Absorption

2 Fatty Acid

+Monoglyceride

DGAT

Triglyceride

www drsarma in


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CE

A-I

CE

A-I

CE

A-II A-II

HDL 1 HDL 2 HDL 3

APO A IAtheroprotective

Alcohol increasesAthero-neutral

The soldiers

The soldier-like

HDL Sub types


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LIVER

Reverse Cholesterol Transport

MF in Vascular

Endothelium

Free Chol.

L CAT

Enzyme

UECEC

HDL


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HDL Metabolism and

Reverse Cholesterol Transport

Liver

ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I;

CE = cholesteryl ester; FC = free cholesterol;

LCAT = lecithin:cholesterol acyltransferase;

SR-BI = scavenger receptor class BI

Mature HDL

CE

A-I

CE

CEFCFC

LCATFC

Bile

SR-BI

A-I

ABC1

MacrophageNascent

HDL


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B

SRA

Mature HDL

Role of CETP in HDL Metabolism

A-I

Liver

CE

CEFC

FC

LCATFC

Bile

SR-BI

A-I

ABC1

Macrophage

CE

CETP = cholesteryl ester transfer protein

LDL = low-density lipoprotein

LDLR = low-density lipoprotein receptor

VLDL = very-low-density lipoprotein

LDLR

VLDL/LDL

CETP

Nascent HDL

CE

Torcitrapib

X


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Hyperlipidemias

Secondary 95%

Primary 5%

Familial & genetic


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Clinical Action

Presence of secondary causesof Hyperlipidemia Order for full lipid profile (LP)HT also

Presence of hyperlipidemiaincreased TG or EC

Investigate for all secondary causes For all above 20 years once in every 5 years

For those above 45 yrsonce in 2 years

For those with already known lipid abnormality

follow-up every 3-6 months Extended Lipid profile includes Homocysteine,

LP(a), SD-LDL, ALP, Apo A and Apo B, hS-CRP

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Clinical Photoes

Tuberous xanthoma.

Flat-topped, yellow, firm tumor

Xanthelasma. Multiple, longitudinal, creamy-

orange, slightly elevated papules on eyelids .

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Clinical Photoes

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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The Weapons in our hand

Dietand Exercise (Life Style)

Drug therapy

1. HMGCo A Reductase Inhibitors

2. Fibric Acid derivatives

3. Nicotinic Acid

4. Ezetimibe

5. Bile Acid binding Resins (BAR)

6. Probucol

HMG is Hydroxy Methyl Glutaryl

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New Treatments

Drug therapy

1. Colesevelam (BAR)

2. Phytosterols

3. AvasimibeACAT inhibitor

4. TorcetrapibCETP inhibitor

5. Drugs decreasing Apo B synthesis6. Selective LDL apopheresis

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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 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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Our dietary fats

SFA (saturated)meet and diary products,

coconut oil, Kernel, Ghee, Butter, Palm oil,

Trans fatty acids in vanaspati, chocolates

confectionaries, baked, deep fat fried food

MUFA (N1)Olive oil, Gingili oil

PUFA (N6)Soya, Sun Flower oil, GN oil

PUFA (N3)Fish oilsTwice a wk 76% CAD

Legumes, fruits, olive oil all cause mortality

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Treatment of LDLc

High LDLc

Therapeutic Lifestyle Change

Add on drug - EZ , Niacin, BAR

Therapy of Choice: Statin

Drug Therapy

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StatinsMechanism of Action

1. Reduce hepatic cholesterol synthesis (HMG CoA),

2. lowering intracellular cholesterol,

3. Upregulation of LDL receptor and

4. the uptake of non-HDL from circulation.

LDL receptormediated

hepatic uptake of LDL

and VLDL remnants

Serum VLDL remnants

Serum LDL-C

Cholesterol

synthesisLDL receptor

(BE receptor)

synthesisIntracellular

Cholesterol

Apo B

Apo E

Apo B

Systemic CirculationHepatocyte

LDL

Serum IDL

VLDLR

VLDL

HMGCoA

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Time course of Statin effects

* Time course establishedDays Years

LDL-Clowered*

Inflammationreduced

Vulnerable

plaquesstabilized

Endothelial

functionrestored

Ischemic

episodesreduced

Cardiac events

reduced*

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HMG C A R d


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HMG CoA Reductase

Inhibitors (Statins)

Statin Dose Range

Lovastatin 2080 mg

Pravastatin 2040 mg

Fluvastatin 2080 mg

Simvastatin 2080 mg

Atorvastatin 1080 mg

Rosuvastatin 520 mg

Cerivastatin 0.40.8 mg

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Atorvastatin211 mg/dl*

Simvastatin

219 mg/dl*

-60%

-50%

-40%

-30%

-20%

-10%

0%

LDL-C Lowering - Statin Dose

Adapted from Jones P et al.Am J Cardiol1998;81:582-587.

Daily Dose

10 mg

20 mg

40 mg

80 mg16% with

3 Titrations

13%

38%

46%

51%

54%

28%

35%

41%

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HMG CoA Reductase Inhibitors (Statins)

Common side effects

Headache, Myalgia, Fatigue, GI intol. Flu-like symptoms

Increase in liver enzymesserious problems are very rare

Occurs in 0.5 to 2.5% of cases in dose-dependent manner

Myopathy occurs in 0.2 to 0.4% of patients Rare cases of Rhabdomyolysis

We can reduce this risk by

Cautiously using statins in impaired renal function

Using the lowest effective dose

Cautiously combining statins with fibrates

Muscle toxicity requires the discontinuation of statin

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Short falls of Statins

Effectiveness and community impact are to be improved

Rebound increase in lipids and of events after

withdrawal of statin Rx.

High rate of discontinuation by patients

Differences in the efficacy of different statins

They reduce only endogenous lipidsIndividual variation

Modest effect on TG and HDL, No effect on Lp(a)

No effect on chylomicrons; escape phenomenon

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Ezetimibe

Cholesterol

NPC1L1

CholesterylEster ABCG5/G8

ACAT

Ezetimibe

X

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Dual Inhibition

Duodenum

Jejunum

Ileum

CM

apoB48

Liver

CMRemnantapoB48

VLDLapoB100

EzetimibeX

LDLapoB100

XStatin

Colon

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Ezetimibe Efficacy (10 + 10 = 80)

Ballantyne CM et al. Circulation 2003;107:2409-2415.

Atorvastatin

40 mg

(n=66)

20 mg

(n=60)

10 mg

(n=60)

53%

37%42%

45%

54%

P < 0.01

80 mg

(n=62)

-60%

-50%

-40%

-30%

-20%

-10%

0%

Ezt + Ator

10+10 mg(n=65)

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Bile Acid Resins: Mechanism of Action

Net Effect - LDL-C

Gall Bladder

LDL Receptors

VLDL and LDL removal

Cholesterol 7- hydroxylaseConversion of cholesterol to BA

BA Secretion

Liver

BA Excretion

Terminal Ileum

Bile Acid

Enterohepatic Recirculation

Reabsorption of

bile acids

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Bile Acid Resins (BAR)

Major actions Reduce LDLc by 1530%

Raise HDLc by 35%

May increase TG

Side effects GI distress / constipation / nausea

Decreased absorption of other drugs

Contra indications

Dysbetalipoproteinemia,

Biliary Obstruction

Raised TG (especially >400 mg/dL)

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Bile Acid Resins

Drug Dose Range

Cholestyramine 416 g

Colestipol 520 g

Colesevelam 2.63.8 g

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T f HDL


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Treatment of HDLc

Low HDLc


Add on drug - Finofibrate

Therapy of Choice : Niacin

Drug Therapy

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C f L HDL


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Causes of Low HDLSmoking

Obesity (visceral fat), Physical inactivity

Very high Carbohydrate diet

Type II Diabetes

Hyper-triglyceridemia

Drugs like beta-blockers, androgenic steroids

and androgenic progestins

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Nicotinic AcidMechanism of Action

Liver CirculationHDL

Serum VLDL

results in reduced

lipolysis to LDL

Serum LDL

VLDL

Decreases hepatic production of VLDL and of apo B

VLDLsecretion

Apo B

Hepatocyte Systemic Circulation

Mobilization of FFA

TG

synthesis

VLDL

LDL

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Eff f Ni i Li i


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Effect of Niacin on Lipoproteins

Adapted from Knopp RH. N Engl J Med 1999;341:498-511..

0 1 g / d 2 g / d 3 g / d

Baseline

-15%

12.5%

25%

-30%

HDL-C with Niaspan

TG with Niaspan

TG with crystalline niacin

LDL-C with Niaspan

LDL-C with crystalline niacin

35%HDL-C with crystalline niacin

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Ni ti i A id


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Nicotinic Acid Products available

Immediate-release, 24 g/d, Sustained Release 3 g /d Extended-release (Niaspan) 12 g/d

Best agent to raise HDL-C

Reduces coronary events

Adverse effects

Flushing, itching, headache (immediate-release, Niaspan)

Hepatotoxicity, GI (sustained-release)

Activation of peptic ulcer

Hyperglycemia and reduced insulin sensitivity

Contraindications

Active liver disease or unexplained LFT elevations

Peptic ulcer disease

Coronary heart disease and HDL C


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Coronary heart disease and HDL-C

Framingham Heart Study

Gordon, Castelli et al. Am J Med 1977; 62: 707714

0

50

100

150

200

Rate/

1000


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Relative risks of MI

3.21

3.78

1.00

2.41Low HDL cholesterol


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HDL-C vs LDL-C

as a predictor of CHD risk

*Men aged 5070 Gordon, Castelli et al. Am J Med 1977; 62: 707714

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

0.5

1

1.5

2

2.5

3

Risk of CAD over 4

years 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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T f TG


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Treatment of TG

High TG


Add on drugStatin, Niacin

Therapy of Choice : Fibrate

Drug Therapy

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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 2004 Guidelines by expert panel on TG

F fib t


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Fenofibrate

Mode of Action Enhances the activity of lipoprotein lipase

Reduces hepatic fatty acid synthesis

Inhibits HMG co-enzyme A reductase activity

Reduces the CETP activity

Increases the LCAT activity Increases the production of Apo AI and Apo A II

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Fibric Acid Derivatives

Major actions

Lower TG 2050%,VLDL synthesis

Raise HDL-C 1020%

LDL (TG is N), LDL (TG is ) Increase the SDL particle size (less athero)

Side effects

Dyspepsia, gallstones, myopathy, Abn. LFT Contraindications

Severe renal or hepatic / biliary disease

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Fibric Acid Derivatives

Drug Dose

Clofibrate 1000 mg BID

Bezafibrate 200 mg BIDGemfibrozil 600 mg BID

Fenofibrate 200 mg OD

Fenofibrate micronized 160 mg OD

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T t t f LDL + TG


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Treatment of LDL + TG

Combined


Add on drugNiacin, BAR

Therapy of Choice : Statin + Fibrate

Drug Therapy

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Statin + Fibrate


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Da Col PG et al. Curr Ther Res Clin Exp 1973;53:473-482.

Statin + Fibrate

-60

-50

-40

-30

-20

-10

0

10

20

30

Simva +

Gemfibrozil

50%

39%

16%22%

41%

28%

Ator or Simva +

Fenofibrate

230 332

38

191166

LDLTG

HDL

LDL

TG

HDL

PercentChange

34

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Statin + FibratePrecautions

Use statin alone for non-HDL-C goals

Use fish oils or niacin rather than fibrates

Keep the doses of the statin and fibrate low

Dose the fibrate in the AM and the statin in the PM

Avoid (or cautiously use) combo in renal impairment

Teach the patient to recognize muscle symptoms

Discontinue therapy if muscle symptoms are present

and CK is >10 times the upper limit of normal

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Probucol

1. Probucol (Lorelco) 500mg b.i.d with food

2. Third line drugerratic effect on LDL & HDL

3. Lowers Cholesterol and the only drug which

regresses xanthomas

4. It is an antioxidant of LDL

5. Diarrohea, flatulence, nausea, increases QTc

6. Can be combined with BAR

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The Three Canons

LDL - STATIN

DYSLIPIDEMIA

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How do we treat ?

Increased LDL Statins +/- EZ

Increased TG Fibrates

Decreased HDL Niacin

Increased Lp(a) Niacin

Increased LDL + TG Statin + Fibrate

LDL + HDL Statin + Niacin TG + HDL Fibrate + Niacin

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Summary of Drug choice


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Lipid abnormality type First choice Additional Remarks

LDL Statin Ezetimibe Myopathy

TG Fibrate Niacin CHO intake

HDL Niacin Fibrate Exercise

LDL + TG Statin + Fibrate Niacin Myo risk

LDL + HDL Statin + Niacin Fibrate Exercise

TG + HDL Fibrate + Niacin Statin Exercise

LDL + TG + HDL Statin + Fibrate E, N, BA, FO Myo risk

Atherogenecity of small dense LDL


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Atherogenecity of small, dense LDL

SDL is highly atherogenic. It

Generates free radicals

Increases trans endothelial filtration

Increases susceptibility to oxidation

Reduces affinity for the LDL receptor

Increased binding to intimal proteoglycan

Formation of pro-aggregators / vasoconstrictors

Impaired in vivo ED independent of HDL, LDL, TG

Circulation, 2000, 102: 716-721

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L ( ) Li l


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Lp(a) or Littlea

Similar to LDL molecule

Apo B + additional Apo a attached by S=S bond

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, ? Bezafibrate, Estrogens it

Phenotype B or ALP


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This ALP or phenotype B is present andseen in most often

Insulin resistant individuals

Diabetics Obese persons

Sedentary life style

More prevalent in India

Apo A I Apo B will be < 1

Phenotype B or ALP

Cumulative Distribution of TG Levels


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0

10

20

30

40

50

60

70

80

90

100

20 40 60 80 100120 140160180200 220240 260280 300 500

Phenotype A

Phenotype B

% Cumulative

frequency

TG (mg/dL)

Phenotypes A and B

Austin M et al. Circulation. 1990;82:495-506.

Cumulative Distribution of HDL levels


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20 25 30 35 40 45 50 55 60 65 70 75 80

Phenotype A

Phenotype B

% Cumulativefrequency

HDL-C (mg/dL)

10090

80

70

60

50

40

30

20

Phenotypes A and B

Austin M et al. Circulation. 1990;82:495-506.

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Homocysteine

Normal value is up to 10 mols./L

Folic acid, Vitamin B6and B12are 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. B6and B12are to be

given on regular basis

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Lipid abnormality type Advised Rx. Remarks

Homocysteine Folic acid B6+ B12helps

Small dense LDL Statin + Fibrate Aggressive Rx.

Little a or LP(a) Niacin Statin no effect

Phenotype B Under research DM, Obesity

in Phenotype A Under research Aerobic exercise


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Ath l i d IR d DM


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Atherosclerosis and IR and DM

Hypertension

Obesity

Hyperinsulinemia

Diabetes

Hypertriglyceridemia

Small, dense LDL

Low HDL

Hypercoagulability

Insulin

ResistanceAtherosclerosis

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Elevated TG

Elevated VLDL

Reduced HDL-C Increase in SD-LDL

Decrease in Apo A I

Increase in Apo B

Ratio of Apo B / Apo 1 > 2

Dyslipidemia in IR and DM

All Diabetics must be given STATIN

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Diabetes Treatment and Lipids


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Diabetes Treatment and Lipids

Type Rx used Effect on lipids

1. Insulin Favourable

2. Metformin Mildly favourable

3. Sulfonylureas Not favourable

4. Glitazones Favourable

5. Acarbose No effect

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Hypertension Treatment and Lipids

Type Rx used Effect on lipids

1. Diuretics Unfavourable

2. Indapamide Mildly favourable

3. ACEi and ARB Very favourable

4. Betablockers Unfavourable

5. Ca channel blockers No effect

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Web Resources on Lipids

www.lipidsonline.org

www.hypertensiononline.org

www.ncbi.nlm.nih.gov

www.univbaylore.org

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Announcements

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CD ROM Available

The contents of my todays presentations

are made available in a CD-ROM format

This CD, in addition, contains my talks on

Asthma, COPD, Hypertension, ECG, CAD

Dyslipidemias, Diabetes, Osteoporosis

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dyslipidemia update by dr sarma

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