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Welcome to You All. Dyslipidemias Dx. and Rx. Dr.Sarma RVS N, M.D., M.Sc (Canada) Consultant in Medicine and Chest, President IMA – Tiruvallur Branch # 3, Jayanagar, Tiruvallur – 602 001 +91 98940 60593, (411 6) 260593. CD ROM Available. The contents of today’s presentation

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Welcome to You All

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Dyslipidemias Dx. and Rx.

Dr.Sarma RVSN, M.D., M.Sc (Canada)

Consultant in Medicine and Chest,

President IMA – Tiruvallur Branch

# 3, Jayanagar, Tiruvallur – 602 001

+91 98940 60593, (4116) 260593

[email protected]


Cd rom available l.jpg
CD ROM Available

The contents of today’s presentation

are available in a CD-ROM format

for computer and VCD player use.

This CD, in addition, contains our talks on

ECG, Asthma, COPD, Hypertension Rx. also

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Adult treatment panel iii atp iii guidelines 2002 updated october 2004 l.jpg

Adult Treatment Panel III (ATP III) Guidelines -2002Updated October 2004

National Cholesterol

Education Program - NCEP

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Guidelines that aren t implemented never work l.jpg
Guidelines that aren’t implemented never work

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CHD Risk Factors ranking - PROCAM Study

Smoking 2.3 0.001

LDL cholesterol (mg%)

> 100 but < 160 1.9 0.01

> 160 4.3 0.001

Hypertension (SBP > 140; DBP > 90) 1.8 0.001

HDL cholesterol (mg%)

40 to 55 1.7 0.01

< 40 2.7 0.001

Triglycerides (mg%)

105- 167 1.6 0.01

>167 2.6 0.001

Fasting blood glucose (mg%)

110 - 126 1.4 0.05

> 126 1.9 0.01

Family history of MI 1.4 0.05

Risk factor Relative risk P Value


Emerging risk factors l.jpg
Emerging Risk Factors

  • Lipoprotein (a)

  • Homocysteine

  • Prothrombotic factors

  • Pro-inflammatory factors

  • Metabolic syndrome

  • Sub-clinical atherosclerosis

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CHD Risk Equivalents

  • Diabetes Mellitus

  • Peripheral Vascular Disease

  • > 20% in Framingham risk score

  • Carotid atheroma

  • Reno-vascular Disease

    All forms of AVD

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AVD – Clinical Manifestations

For every thing the common denominator is ED

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Progression of Atherosclerosis

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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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The havoc by ldl at the endothelium l.jpg
The Havoc by LDL at the endothelium

Vessel Lumen

Monocyte

LDL

AdhesionMolecules

Endothelium

MCP-1

LDL

Intima

Modified LDL

Cytokines

Growth FactorsMetalloproteinases

Cell ProliferationMatrix Degradation

Macrophage

Foam Cell

Ross R. N Engl J Med 1999;340:115-126.


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Vulnerable Atherosclerotic Plaque

Non-Vulnerable Atherosclerotic Plaque

Pathogenesis of ACS



Lipid transport l.jpg

TG

EC

Apoprotein boat

Lipid Transport

Apo A I and A II for HDLApo B100 for LDL, Lp(a)

Apo B100+C+E – VLDL, IDLApo B48+C+A+E – Chy. microns

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Lipoproteins l.jpg

HDL

A I, A II

B 100

TG

TG

C

TG

TG

C

C

B 48+E+C

CM

B 100 + E +C

Lipoproteins

LDL

VLDL

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Cholesterols and apoproteins l.jpg
Cholesterols and Apoproteins

  • Total Cholesterol < 200 Apoprotein

  • ‘Bad’ CholesterolsApo B type

    • LDLc, IDLc < 100 B100 or B100 +E

    • VLDLc, VLDLr < 30 B100 + E + C

    • Lp(a), small LDL < 20 B100 + (a)

  • ‘Good’ Cholesterols Apo A type

    • HDL 1, HDL 2, HDL 3 > 50 A I and A II

HDL 1 and HDL 2 are protective

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Chylomicrons

<< 1.006

VLDL

< 1.006

IDL

< 1.019

LDL

Small LDL

HDL

< 1.063

< 1.085

< 1.210

Particle size & Density

Atherogenicity increases as density increases

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Atherogenic Particles

Apolipoprotein B

Measurements

Non-HDL-C

VLDL

VLDLR

IDL

LDL

SDL

TG-rich lipoproteins

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Two Types of Lipids

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Lipid Profile Report

PP

Fasting

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Lipid Calculations

200

  • Total Cholesterol

    HDL Cholesterol

    LDL Cholesterol (TC –(HDL+VLDL))

    VLDL Cholesterol (1/5 of TG)

    B. Triglycerides

50

120

30

150

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The Good and Bad

  • Total Cholesterol < 200

  • ‘Good’ Cholesterols

    • HDL 1, HDL 2, HDL 3 > 50

  • ‘Bad’ Cholesterols (Non HDLc) < 150

    • LDLc, IDLc < 100

    • VLDLc, VLDLr < 30

    • Lp(a), small LDL < 20

HDL 1 and HDL 2 are protective

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How it should be reported ?

Interpretation HDL – N,LDL – High , TG - HIGH

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Today’s Safer Values

  • Total Cholesterol < 200

  • Triglycerides < 150

  • LDL Cholesterol < 100

  • HDL Cholesterol > 50 (for women 55)

  • Bad Cholesterols the lower the better

  • Good Cholesterols the higher the better

  • Non HDL Cholesterol < 130

  • Lp(a) values < 20

  • Homocysteine < 14 μ mols per liter

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Indian Specialty

A. Isolated low LDL 32.90%

B. Isolated low HDL 21.35%

C. Isolated high TG 10.45%

↑TG

↑LDL

The Triad

↓HDL

IHJ, 2000, 52: 173-177

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

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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 lipids are one aspects

  • Tissue lipid content is more important

    J. Atherosclerosis : Hopkins PN, 1997 – 17, 2792

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Relative risk of CHD

1.6

6

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Intestinal cholesterol absorption l.jpg

CM

MTP

ACAT

Intestinal Cholesterol Absorption

Biliarycholesterol

Dietarycholesterol

Intestinal epithelial cell

Through lymphatic system to the liver

Luminalcholesterol

Cholesteryl esters

Bile acid

excretion

(esterification)

ABCG5ABCG8

Micellarcholesterol

Freecholesterol

uptake

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

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Cholesterol absorption l.jpg
Cholesterol Absorption

Lymph

Enterocyte

IntestinalLumen

Ezetimibe

Cholesterol

NPC1L1

ACAT

CholesterylEster

ABCG5/G8

Avasimibe

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Fat absorption l.jpg

Liver

Duodenum

BiliaryTransportand Storage

Jejunum

Ileum

Colon

Fat Absorption

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Triglyceride absorption l.jpg
Triglyceride Absorption

Lymph

Enterocyte

IntestinalLumen

2 Fatty Acid

+

Monoglyceride

DGAT

Triglyceride

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Chylomicron Formation

Lymph

Enterocyte

IntestinalLumen

CM

apoB48

Triglyceride

CholesterylEster

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Structure of HDL Particle

A-I

A-I

CE

TG

A-II

A-I, A-II = apolipoprotein A-I, A-II; CE = cholesterol ester; TG = triglycerides

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Hdl types l.jpg

A-I

CE

HDL Types

A-I

CE

CE

A-II

A-II

HDL 1

HDL 2

HDL 3

APO A I Protective

Alcohol increases

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Reverse cholesterol transport l.jpg

MF in Vascular Endothelium

LIVER

EC

Free Chol.

HDL

Reverse Cholesterol Transport

UEC

L CAT Enzyme

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Hdl metabolism and reverse cholesterol transport l.jpg

A-I

CE

HDL Metabolism and Reverse Cholesterol Transport

Bile

A-I

FC

CE

CE

LCAT

FC

FC

ABC1

Nascent HDL

SR-BI

Macrophage

Liver

Mature HDL

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

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Role of CETP in HDL Metabolism

Bile

Macrophage

Nascent HDL

Mature HDL

A-I

A-I

FC

CE

CE

LCAT

FC

CE

ABC1

FC

SR-BI

SRA

CETP

X

Liver

LDLR

Oxidation

CE

B

VLDL/LDL

CETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein

Torcitrapib

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Hyperlipidemias

Primary 5%

Familial & genetic

Secondary 95%

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Secondary Hyperlipidemia

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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

  • For those above 45 yrs – once 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

  • History of eruptive xanthomas, Abd. pain

  • H/o wt. gain, DM, estrogens, Alcohol, Ex.

  • Fasting Lipid profile (TC, LDL, HDL, TG)

  • OGTT, TSH, Liver & Renal Function tests

  • CHD assessment by ECG, TMT, Angio

  • Risk factor assessment, Family H/o P.CHD

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Treatment strategy l.jpg
Treatment Strategy

Lipid Profile, Risk Assessment

LDL > 100

Look For Sec. Causes

Treat the cause, if found

Treatment

NO CHD

CHD +

Primary Prevention

Sec. Prevention

LDL < 130

2 or more RF

< 2 RF

Low Risk

High Risk

LDL > 100

LDL <160

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Treatment Plan - LDLc

For Indians all the values must be 20 mg less

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Treatment Options

  • Diet – Two step approach

  • Drug therapy

    • HMG¢co A Reductase Inhibitors

    • Fibric Acid derivatives

    • Nicotinic Acid

    • Ezetimibe

    • Bile Acid binding Resins (BAR)

    • Probucol

¢HMG is Hydroxy Methyl Glutaryl

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New Treatments

Drug therapy

  • Colesevelam (BAR)

  • Phytosterols

  • Avasimibe – ACAT inhibitor

  • Torcetrapib – CETP inhibitor

  • Drugs decreasing Apo B synthesis

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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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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 oils – Twice a wk ↓ 76% CAD

  • Legumes, fruits, olive oil – ↓ all cause mortality

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Treatment of ↑LDLc

High LDLc

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice: Statin

Add on drug - EZ , Niacin, BAR

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Statins mechanism of action l.jpg

VLDL

Cholesterol synthesis

Apo B

LDL receptor

(B–E receptor)

synthesis

VLDLR

LDL receptor–mediated hepatic uptake of LDL and VLDL remnants

Apo E

Serum LDL-C

Intracellular Cholesterol

Apo B

LDL

Serum VLDL remnants

Serum IDL

Hepatocyte

Systemic Circulation

Statins – Mechanism of Action

HMGCoA

  • Reduce hepatic cholesterol synthesis (HMG CoA),

  • lowering intracellular cholesterol,

  • Upregulation of LDL receptor and

  • ↑ the uptake of non-HDL from circulation.

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CHD Risk Reduction – Statin Therapy

Relative Risk Reduction (%)

+20

0

–5

–10

–15

–20

–25

–30

–35

–40

–45

–50

Endpoints

Major coronary events

Coronary deaths

Cardiovascular deaths

Noncardiovascular events

Total mortality

Strokes

Intermittent claudication

Angina

La Rosa JC et al. JAMA 1999;282:2340-2346.

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Time course of Statin effects

Vulnerableplaquesstabilized

LDL-C lowered*

Inflammationreduced

Endothelialfunctionrestored

Ischemicepisodesreduced

Cardiac eventsreduced*

Days

Years

* Time course established

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Hmg coa reductase inhibitors statins l.jpg
HMG CoA Reductase Inhibitors (Statins)

Statin Dose Range

Lovastatin 20–80 mg

Pravastatin 20–40 mg

Fluvastatin 20–80 mg

Simvastatin 20–80 mg

Atorvastatin 10–80 mg

Rosuvastatin 5–20 mg

Cerivastatin 0.4–0.8 mg

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Ldl c lowering statin dose l.jpg

10 mg

20 mg

40 mg

80 mg

LDL-C Lowering - Statin Dose

Atorvastatin211 mg/dl*

Simvastatin219 mg/dl*

Daily Dose

Mean % Change from Baseline

28%

38%

35%

13%

41%

46%

16% with3 Titrations

51%

54%

Adapted from Jones P et al. Am J Cardiol 1998;81:582-587.

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HMG CoA Reductase Inhibitors (Statins)

  • Common side effects

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

  • Increase in liver enzymes – serious 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 lipids – Individual variation

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

  • No effect on chylomicrons; escape phenomenon

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Ezetimibe l.jpg
Ezetimibe

Lymph

Enterocyte

IntestinalLumen

Ezetimibe

Cholesterol

X

NPC1L1

ACAT

CholesterylEster

ABCG5/G8

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Dual inhibition l.jpg

X

Ezetimibe

Dual Inhibition

LDLapoB100

Liver

Statin

Duodenum

X

VLDLapoB100

Jejunum

Ileum

CM RemnantapoB48

CM

apoB48

Colon

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Slide61 l.jpg

Atorvastatin

Ezt + Ator

10+10 mg

(n=65)

Mean % Change in LDL-C from Baseline

10 mg(n=60)

20 mg(n=60)

40 mg(n=66)

80 mg(n=62)

–37%

–42%

–45%

–53%

–54%

P < 0.01

Ezetimibe Efficacy (“10 + 10 = 80”)

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


Bile acid resins mechanism of action l.jpg

  • Cholesterol 7- hydroxylase

  • Conversion of cholesterol to BA

  • BA Secretion

Gall Bladder

Bile Acid

Enterohepatic Recirculation

Liver

Terminal Ileum

  • LDL Receptors

  • VLDL and LDL removal

Reabsorption of bile acids

  • BA Excretion

Net Effect -  LDL-C

Bile Acid Resins: Mechanism of Action

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Bile Acid Resins (BAR)

Major actions

  • Reduce LDLc by 15–30%

  • Raise HDLc by 3–5%

  • 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 l.jpg
Bile Acid Resins

Drug Dose Range

Cholestyramine 4–16 g

Colestipol 5–20 g

Colesevelam 2.6–3.8 g

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Treatment of h dlc l.jpg
Treatment of ↓ HDLc

Low HDLc

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Niacin

Add on drug - Finofibrate

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Slide66 l.jpg

Prevalence of coronary heart disease and its risk factors in Asian Indians

Atherosclerosis , Rosemount , IL Oct 6-11 , 1991

The CADI study [Coronary Artery Disease in Asian Indians]

14% of Asian Indian males & 5% of females have Optimal HDL

In Indian patients with CAD, High TG levels are found more often than high cholesterol levels.

Journal, Ind. Acad. clin. med vol 2 Jul-Sept 2001


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Causes of Low HDL Asian Indians

  • Smoking

  • 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 acid mechanism of action l.jpg

LDL Asian Indians

Nicotinic Acid – Mechanism of Action

Mobilization of FFA

Apo B

Serum VLDL results in reduced lipolysis to LDL

VLDL

VLDL

TG synthesis

VLDL secretion

Serum LDL

HDL

Liver

Circulation

Hepatocyte

Systemic Circulation

Decreases hepatic production of VLDL and of apo B

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Effect of niacin on lipoproteins l.jpg

35% Asian Indians

HDL-C with crystalline niacin

25%

HDL-C with Niaspan®

12.5%

Baseline

LDL-C with Niaspan®

LDL-C with crystalline niacin

-15%

TG with Niaspan®

-30%

TG with crystalline niacin

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

Effect of Niacin on Lipoproteins

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


Nicotinic acid l.jpg
Nicotinic Acid Asian Indians

  • Products available

    • Immediate-release, 2–4 g/d, Sustained Release 3 g /d

    • Extended-release (Niaspan®) 1–2 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

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Coronary heart disease and hdl c framingham heart study l.jpg
Coronary heart disease and HDL-C Asian Indians Framingham Heart Study

200

150

Rate/1000

100

Women

50

Men

0

<25

25–34

35–44

45–54

55–64

65–74

75+

HDL-C (mg/dl)

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


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Relative risks of MI Asian Indians

The Physicians Health Study

3.78

3.21

Low HDL cholesterol

<47 mg/dl

2.41

1.00

High HDL cholesterol

47 mg/dl

Low total cholesterol

<212 mg/dl

High total cholesterol

212 mg/dl

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


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HDL-C vs LDL-C Asian Indians 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 50–70

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


Management of low hdlc l.jpg
Management of Low HDLc Asian Indians

  • 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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Treatment of tg l.jpg
Treatment of Asian Indians ↑TG

High TG

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Fibrate

Add on drug – Statin, Niacin

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Treatment Strategy Asian Indians

Fasting TG Level

TG < 150

Normal

↑Fasting TG Level

< 2 RF

Diet Modify

TG >150, No CHD

2 or > RF

Diet + Fibrate

TG > 150, CHD +

Diet + Fibrate + Niacin

TG > 500, CHD +/-

Diet + Fibrate + Statin

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Triglycerides Asian Indians

NCEP 2002 Guidelines by expert panel on TG

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Fenofibrate Asian Indians

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 Asian Indians

  • Major actions

    • Lower TG 20–50%,↓VLDL synthesis

    • Raise HDL-C 10–20%

    • ↓ 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 Asian Indians

Drug Dose

Clofibrate 1000 mg BID

Bezafibrate 200 mg BID

Gemfibrozil 600 mg BID

Fenofibrate 200 mg OD

Fenofibrate micronized 160 mg OD

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Treatment of ldl tg l.jpg
Treatment of Asian Indians ↑ LDL + ↑TG

Combined

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Statin + Fibrate

Add on drug – Niacin, BAR

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Statin + Fibrate Asian Indians

Simva +Gemfibrozil

Ator or Simva +Fenofibrate

22%

16%

HDL

HDL

230

332

166

191

38

34

Percent Change

LDL

LDL

TG

TG

–28%

–39%

–41%

–50%

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

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Statin + Fibrate – Precautions Asian Indians

  • 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 Asian Indians

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

  • Third line drug – erratic effect on LDL & 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 BAR

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Asian Indians HDL - NIACIN

↑ TG - FIBRATE

↑ LDL - STATIN

The Three Canons

DYSLIPIDEMIA

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Summary of Drug choice Asian Indians

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Atherogenecity of small, dense LDL Asian Indians

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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Lp(a) or Little‘a’ Asian Indians

  • 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

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Phenotype B or ALP Asian Indians

  • This ALP or phenotype B is present and seen in most often

    • Insulin resistant individuals

    • Diabetics

    • Obese persons

    • Sedentary life style

  • More prevalent in India

  • Apo A I ÷ Apo B will be < 1


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Cumulative Distribution of TG Levels Phenotypes A and B Asian Indians

100

90

80

70

60

% Cumulativefrequency

50

40

Phenotype A

30

Phenotype B

20

10

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

500

TG (mg/dL)

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


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Cumulative Distribution of HDL levels Phenotypes A and B Asian Indians

100

90

80

70

60

% Cumulativefrequency

50

Phenotype A

40

Phenotype B

30

20

20

25

30

35

40

45

50

55

60

65

70

75

80

HDL-C (mg/dL)

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



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The interaction between our current genotype and our present day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

Journal of Internal Medicine 2003:254(2):114-25


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ATP-III Criteria for Metabolic Syndrome day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

  • Abdominal obesity (waist circumference): men >100 cm (40 in); women >88 cm (35 in)

  • Triglycerides > 150 mg/dl

  • HDL cholesterol: men < 40 mg/dl; women < 50 mg/dl

  • Blood pressure > 130/ 85 mmHg.

  • Fasting glucose > 110 mg/dl

Diagnosis of metabolic syndrome is made when 3 or more of the risk determinants shown above are present.


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Homocysteine day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

  • Normal value is up to 15 μmols./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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Summary of Drug choice day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

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Some Brand Names day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

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Atherosclerosis and IR and DM day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

Hypertension

Obesity

Hyperinsulinemia

Diabetes

Hypertriglyceridemia

Small, dense LDL

Low HDL

Hypercoagulability

InsulinResistance

Atherosclerosis

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Dyslipidemia in IR and DM day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

  • Elevated TG

  • Elevated VLDL

  • Reduced HDL-C

  • Increase in SD-LDL

  • Decrease in Apo A I

  • Increase in Apo B

  • Ratio of Apo A I / Apo B < 1

All Diabetics must be given STATIN

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Diabetes Treatment and Lipids day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

Type Rx used Effect on lipids

  • Insulin Favourable

  • Metformin Mildly favourable

  • Sulfonylureas Not favourable

  • Glitazones Favourable

  • Acarbose No effect

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Hypertension treatment and lipids l.jpg
Hypertension Treatment and Lipids day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

Type Rx used Effect on lipids

  • Diuretics Unfavourable

  • Indapamide Mildly favourable

  • ACEi and ARB Very favourable

  • Betablockers Unfavourable

  • Ca channel blockers No effect

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Who is to be blamed ?? day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

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20000 B.C. day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

2004

Paleolithic sup. age

Neolithic age

19th century

21st century

Processed

foods

Hunting-gathering

subsistence

Animal fats

­

and glucides

Dietary fibre

¯

High level of

Sedentary

physical activity

life

Thrifty genotype

Susceptibility genotype

Where are we heading ? ?

Technology has changed a lot in the way we live

But, we have not altered our life style

Journal of internal medicine 2003:254(2):114-25


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We have to pay the very heavy price !! day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

What could be prevented, we treat or leave


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Web Resources on Lipids day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

www.lipidsonline.org

www.hypertensiononline.org

www.ncbi.nlm.nih.gov

www.univ baylor.org

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CD ROM Available day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

The contents of today’s presentation

are available in a CD-ROM format

for computer and VCD player use.

This CD, in addition, contains our talks on

ECG, Asthma, COPD, Hypertension Rx. also

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Wishing YOU all day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis.

A HAPPAY NEW YEAR

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