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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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slide2

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
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

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

National Cholesterol

Education Program - NCEP

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chd risk factors ranking procam study
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
Emerging Risk Factors
  • Lipoprotein (a)
  • Homocysteine
  • Prothrombotic factors
  • Pro-inflammatory factors
  • Metabolic syndrome
  • Sub-clinical atherosclerosis

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slide8

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
AVD – Clinical Manifestations

For every thing the common denominator is ED

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lipid peroxidation
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
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.

slide13

Vulnerable Atherosclerotic Plaque

Non-Vulnerable Atherosclerotic Plaque

Pathogenesis of ACS

lipid transport

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

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
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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particle size density

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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slide19

Atherogenic Particles

Apolipoprotein B

Measurements

Non-HDL-C

VLDL

VLDLR

IDL

LDL

SDL

TG-rich lipoproteins

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lipid calculations
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
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
How it should be reported ?

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

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today s safer values
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
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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slide27

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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intestinal cholesterol absorption

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
Cholesterol Absorption

Lymph

Enterocyte

IntestinalLumen

Ezetimibe

Cholesterol

NPC1L1

ACAT

CholesterylEster

ABCG5/G8

Avasimibe

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fat absorption

Liver

Duodenum

BiliaryTransportand Storage

Jejunum

Ileum

Colon

Fat Absorption

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triglyceride absorption
Triglyceride Absorption

Lymph

Enterocyte

IntestinalLumen

2 Fatty Acid

+

Monoglyceride

DGAT

Triglyceride

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chylomicron formation
Chylomicron Formation

Lymph

Enterocyte

IntestinalLumen

CM

apoB48

Triglyceride

CholesterylEster

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structure of hdl particle
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

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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hdl metabolism and reverse cholesterol transport

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
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
Hyperlipidemias

Primary 5%

Familial & genetic

Secondary 95%

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clinical action
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
Clinical Photoes

Tuberous xanthoma. Flat-topped, yellow, firm tumor

Xanthelasma. Multiple, longitudinal, creamy-orange, slightly elevated papules on eyelids .

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clinical photoes43
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
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
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
Treatment Plan - LDLc

For Indians all the values must be 20 mg less

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treatment options
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
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
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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slide50

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
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

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
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
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
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

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 statins57
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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slide58

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
Ezetimibe

Lymph

Enterocyte

IntestinalLumen

Ezetimibe

Cholesterol

X

NPC1L1

ACAT

CholesterylEster

ABCG5/G8

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dual inhibition

X

Ezetimibe

Dual Inhibition

LDLapoB100

Liver

Statin

Duodenum

X

VLDLapoB100

Jejunum

Ileum

CM RemnantapoB48

CM

apoB48

Colon

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slide61

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

 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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slide63

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
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
Treatment of ↓ HDLc

Low HDLc

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Niacin

Add on drug - Finofibrate

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slide66

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

causes of low hdl
Causes of Low HDL
  • 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

LDL

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

35%

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
Nicotinic Acid
  • 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
Coronary heart disease and HDL-CFramingham 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

relative risks of mi
Relative risks of MI

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

hdl c vs ldl c as a predictor of chd risk
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 50–70

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

management of low hdlc
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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treatment of tg
Treatment of ↑TG

High TG

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Fibrate

Add on drug – Statin, Niacin

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treatment strategy76
Treatment Strategy

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
Triglycerides

NCEP 2002 Guidelines by expert panel on TG

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fenofibrate
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
fibric acid derivatives
Fibric Acid Derivatives
  • 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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slide80

Fibric Acid Derivatives

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
Treatment of ↑ LDL + ↑TG

Combined

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Statin + Fibrate

Add on drug – Niacin, BAR

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statin fibrate
Statin + Fibrate

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
Statin + Fibrate – Precautions
  • 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
Probucol
  • 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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the three canons

↓ HDL - NIACIN

↑ TG - FIBRATE

↑ LDL - STATIN

The Three Canons

DYSLIPIDEMIA

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atherogenecity of small dense ldl
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

lp a or little a
Lp(a) or Little‘a’
  • 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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slide89

Phenotype B or ALP

  • 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
cumulative distribution of tg levels phenotypes a and b
Cumulative Distribution of TG Levels Phenotypes A and B

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.

cumulative distribution of hdl levels phenotypes a and b
Cumulative Distribution of HDL levels Phenotypes A and B

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.

slide93
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

atp iii criteria for metabolic syndrome
ATP-III Criteria for Metabolic Syndrome
  • 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.

homocysteine
Homocysteine
  • 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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atherosclerosis and ir and dm
Atherosclerosis and IR and DM

Hypertension

Obesity

Hyperinsulinemia

Diabetes

Hypertriglyceridemia

Small, dense LDL

Low HDL

Hypercoagulability

InsulinResistance

Atherosclerosis

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dyslipidemia in ir and dm
Dyslipidemia in IR and DM
  • 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
Diabetes Treatment and Lipids

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
Hypertension Treatment and Lipids

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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where are we heading

20000 B.C.

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

slide104

We have to pay the very heavy price !!

What could be prevented, we treat or leave

web resources on lipids
Web Resources on Lipids

www.lipidsonline.org

www.hypertensiononline.org

www.ncbi.nlm.nih.gov

www.univ baylor.org

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cd rom available106
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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