Dr.Sarma@works 1 Welcome to You All. Dr.Sarma@works 2 Dr.Sarma RVSN, M.D., M.Sc (Canada) Consultant in Medicine and Chest, President IMA – Tiruvallur.

Dr.Sarma@works

1

Welcome to You

All

Dr.Sarma@works

2

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

Dyslipidemias Dx. and Rx.

Dyslipidemias Dx. and Rx.

Dr.Sarma@works

3

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

Dr.Sarma@works

4

National Cholesterol Education Program - NCEP

Adult Treatment Panel III (ATP III) Guidelines -2002

Updated October 2004

Dr.Sarma@works

5

Guidelines that aren’t implemented never work

Guidelines that aren’t implemented never work

CHD Risk Factors ranking - PROCAM StudyCHD Risk Factors ranking - PROCAM Study

Risk factor Relative risk P ValueRisk factor Relative risk P Value

Smoking 2.30.001

LDL cholesterol (mg%)> 100 but < 160 1.90.01> 160 4.30.001

Hypertension (SBP > 140; DBP > 90) 1.80.001

HDL cholesterol (mg%)40 to 55 1.70.01< 40 2.70.001

Triglycerides (mg%)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

Smoking 2.30.001

LDL cholesterol (mg%)> 100 but < 160 1.90.01> 160 4.30.001

Hypertension (SBP > 140; DBP > 90) 1.80.001

HDL cholesterol (mg%)40 to 55 1.70.01< 40 2.70.001

Triglycerides (mg%)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

Dr.Sarma@works

7

Emerging Risk Factors

1. Lipoprotein (a)

2. Homocysteine

3. Prothrombotic factors

4. Pro-inflammatory factors

5. Metabolic syndrome

6. Sub-clinical atherosclerosis

Dr.Sarma@works

8

CHD Risk Equivalents

1. Diabetes Mellitus

2. Peripheral Vascular Disease

3. > 20% in Framingham risk score

4. Carotid atheroma

5. Reno-vascular Disease

All forms of AVD

Dr.Sarma@works

9

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

Renal HT, Renal impairment

Renal Failure

Leg Muscles

Peripheral Vascular Disease (PVD)

Ischemia

Infarction

Intermittent Claudication

Gangrene

For every thing the common denominator is ED

Dr.Sarma@works

10

Progression of Atherosclerosis

Dr.Sarma@works

11

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

LDL

LDLEndothelium

Vessel LumenMonocyte

Macrophage

AdhesionMolecules

The Havoc by LDL at the endothelium

Foam Cell

IntimaModified

LDLCytokines

Cell ProliferationMatrix Degradation

Growth FactorsMetalloproteinases

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

MCP-1

Pathogenesis of ACS

Non-Vulnerable Atherosclerotic

Plaque

Non-Vulnerable Atherosclerotic

Plaque

Vulnerable Atherosclerotic

Plaque

Vulnerable Atherosclerotic

Plaque

Plaque Rupture with Thrombus Plaque Rupture with Thrombus

Dr.Sarma@works

15

ECTG

Lipid Transport

Apoprotein boat

Apo A I and A II for HDL Apo B100 for LDL, Lp(a) Apo B100+C+E – VLDL, IDL Apo B48+C+A+E – Chy. microns

Dr.Sarma@works

16

Lipoproteins

CTG

B 100 + E +C

CTG

B 100

CTG

A I, A II

HDL LDL

VLDL

TG

B 48+E+C

CM

Dr.Sarma@works

17

Cholesterols and Apoproteins

• Total Cholesterol < 200 Apoprotein • ‘Bad’ Cholesterols Apo 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

Dr.Sarma@works

18

Particle size & Density

Chylomicrons

<< 1.006

VLDL

< 1.006

IDL

< 1.019

LDL

< 1.063

Small LDL

< 1.085

HDL

< 1.210

Atherogenicity increases as density increases

Dr.Sarma@works

19

Atherogenic Particles

Apolipoprotein BApolipoprotein B

Non-HDL-CNon-HDL-CMeasurementsMeasurements

TG-rich lipoproteinsTG-rich lipoproteins

VLDLVLDL VLDLRVLDLR IDLIDL LDLLDL SDLSDL

Dr.Sarma@works

20

Two Types of Lipids

LIPIDS IN BLOOD

TOTAL CHOLESTEROL TRIGLYCERIDES

GOOD CHOLESTEROLHDL 1 and HDL 2

BAD CHOLESTEROLLDL, ( IDL, VLDL, Lp(a))

Dr.Sarma@works

21

LIPIDS ESTIMATED

TOTAL CHOLESTEROL (TC) TRIGLYCERIDES (TG)

HDLc LDLc VLDLc Chylomicrons VLDL

Lipid Profile Report

PP Fasting

Dr.Sarma@works

22

Lipid Calculations

A. Total Cholesterol

HDL Cholesterol

LDL Cholesterol (TC –(HDL+VLDL))

VLDL Cholesterol (1/5 of TG)

B. Triglycerides

150

30

120

50

200

Dr.Sarma@works

23

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

Dr.Sarma@works

24

How it should be reported ?

Lipid type tested Patient Normal

Total Cholesterol (TC) 260 200

HDLc (athero-protective) 55 55

LDLc + other atherogenic 155 100

Non-HDLc (atherogenic) 205 130

Ratio of TC ÷ HDLc 4.73 4

Triglycerides (TG) 250 150

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

Dr.Sarma@works

25

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

Dr.Sarma@works

26

Indian Specialty

A. Isolated low LDL 32.90%B. Isolated low HDL 21.35%C. Isolated high TG 10.45%

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

↑LDL

↓HDL

↑TG

The Triad

Dr.Sarma@works

27

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

Dr.Sarma@works

28

Additive Effect

SBP >160

Dyslipidemia

Smoking

4

3

5

4.5

16

With DM all risks are doubledWith DM all risks are doubled

Relative risk of CHD

1.6

6

Dr.Sarma@works

29

Intestinal Cholesterol Absorption

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

Intestinal Intestinal epithelial cellepithelial cell

BiliaryBiliarycholesterolcholesterol

DietaryDietarycholesterolcholesterol

LuminalLuminalcholesterolcholesterol

MicellarMicellarcholesterolcholesterol

Bile Bile acidacid

Cholesteryl esters

Freecholesterol

excretion

uptakeuptake

ACATACAT

ABCG5ABCG5ABCG8ABCG8

(esterification)

MTPMTPCMCM

Through Through lymphatic lymphatic system to system to the liverthe liver

Dr.Sarma@works

30

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Cholesterol Absorption

Cholesterol

NPC1L1

CholesterylEster ABCG5/G8

ACAT

Ezetimibe

Avasimibe

Dr.Sarma@works

31

Fat Absorption

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

BiliaryBiliaryTransportTransportand Storageand Storage

BiliaryBiliaryTransportTransportand Storageand Storage

ColonColonColonColon

LiverLiverLiverLiver

Dr.Sarma@works

32



Triglyceride Absorption

2 Fatty Acid+

Monoglyceride

DGAT

Triglyceride

Dr.Sarma@works

33



Chylomicron Formation

CholesterylEster

CMapoB48

Triglyceride

Dr.Sarma@works

34

Structure of HDL Particle

A-I A-I

A-II

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

CETG

Dr.Sarma@works

35

HDL Types

CE

A-I

CE

A-I

CE

A-II A-II

HDL 1 HDL 2 HDL 3

APO A I Protective Alcohol increases

Dr.Sarma@works

36

LIVER

Reverse Cholesterol Transport

MF in Vascular Endothelium

Free Chol.

L CAT Enzyme

UECEC

HDL

Dr.Sarma@works

37HDL 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

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABC1Macrophage

Nascent HDL

Dr.Sarma@works

38

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 proteinLDL = low-density lipoprotein

LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein

LDLR

VLDL/LDL

CETP

Nascent HDL

CE

Oxidation

Torcitrapib

X

Dr.Sarma@works

39

Hyperlipidemias

Secondary 95%

Primary 5%Familial & genetic

Dr.Sarma@works

40

Secondary Hyperlipidemia

↑ LDL Cholesterol ↑ TGNephrotic syndrome. ObesityHypothyroidism DiabetesObstr. liver disease UremiaAnorexia nervosa Alcoholism, SmokingAcute Int. Porphyria Oral contraceptivesProgestogens Beta blockersThiazides PregnancyAnabolic steroids Steroids, Thiazides

Dr.Sarma@works

41

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

Dr.Sarma@works

42

Clinical Photoes

Tuberous xanthoma. Flat-topped, yellow, firm tumor

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

Dr.Sarma@works

43

Clinical Photoes

Tendinous xanthomas. Large sub-cutaneous tumors adherent to the Achilles tendons.

Papular eruptive xanthomas. Multiple, discrete, red-to-yellow confluent papules

Dr.Sarma@works

44

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

Dr.Sarma@works

45

Treatment Strategy

Lipid Profile, Risk Assessment

LDL > 100 Look For Sec. CausesTreat the cause, if found

Treatment

Sec. PreventionPrimary Prevention

High Risk Low Risk

LDL < 130

LDL <160

CHD +

NO CHD

< 2 RF 2 or more RF

LDL > 100

Dr.Sarma@works

46

Treatment Plan - LDLc

Clinical Status Goal Diet Drugs

No CHD< 2 RF

<160 >160 >190

No CHD2 or more RF

<130 >130 >160

CHD Present <100 >100 >130

For Indians all the values must be 20 mg less

Dr.Sarma@works

47

Treatment Options

• Diet – Two step approach• Drug therapy

1. HMG¢ co A Reductase Inhibitors2. Fibric Acid derivatives3. Nicotinic Acid4. Ezetimibe5. Bile Acid binding Resins (BAR)6. Probucol

¢ HMG is Hydroxy Methyl Glutaryl

Dr.Sarma@works

48

New Treatments

Drug therapy

1. Colesevelam (BAR)

2. Phytosterols

3. Avasimibe – ACAT inhibitor

4. Torcetrapib – CETP inhibitor

5. Drugs decreasing Apo B synthesis

Dr.Sarma@works

49

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

Dr.Sarma@works

50

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

Dr.Sarma@works

51

Treatment of ↑ LDLc

High LDLcHigh LDLcHigh LDLcHigh LDLc

Therapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Add on drug - EZ , Niacin, BARAdd on drug - EZ , Niacin, BARAdd on drug - EZ , Niacin, BARAdd on drug - EZ , Niacin, BAR

Therapy of Choice: StatinTherapy of Choice: StatinTherapy of Choice: StatinTherapy of Choice: Statin

Drug TherapyDrug TherapyDrug TherapyDrug Therapy

Dr.Sarma@works

52

Statins – Mechanism of Action

1.1. Reduce hepatic cholesterol synthesis (HMG CoA), Reduce hepatic cholesterol synthesis (HMG CoA),

2.2. lowering intracellular cholesterol,lowering intracellular cholesterol,

3.3. Upregulation of LDL receptor and Upregulation of LDL receptor and

4.4. ↑ ↑ the uptake of non-HDL from circulation.the uptake of non-HDL from circulation.

LDL receptorLDL receptor––mediated mediated hepatic uptake of LDL hepatic uptake of LDL and VLDL remnantsand VLDL remnants

Serum VLDL remnantsSerum VLDL remnants

Serum LDL-CSerum LDL-C

Cholesterol Cholesterol synthesissynthesis

LDL receptor LDL receptor

(B(B––E receptor) E receptor)

synthesissynthesisIntracellular Intracellular CholesterolCholesterol

Apo BApo B

Apo EApo E

Apo BApo B

Systemic CirculationSystemic CirculationHepatocyteHepatocyte

LDLLDL

Serum IDLSerum IDL

VLDLVLDLRRVLDLVLDLRR

VLDLVLDL

HMGCoA

Dr.Sarma@works

53

–45

CHD Risk Reduction – Statin Therapy

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

EndpointsEndpoints +20 –35–30–250 –5 –10–15–20Relative Risk Reduction (%)

–40 –50

Major coronary events

Coronary deaths

Cardiovascular deaths

Noncardiovascular events

Total mortality

Strokes

Intermittent claudication

Angina

Dr.Sarma@works

54

Time course of Statin effects

* Time course establishedDaysDays YearsYears

LDL-C LDL-C lowered*lowered*

InflammationInflammationreducedreduced

VulnerableVulnerableplaquesplaques

stabilizedstabilized

EndothelialEndothelialfunctionfunctionrestoredrestored

IschemicIschemicepisodesepisodesreducedreduced

Cardiac eventsCardiac eventsreduced*reduced*

Dr.Sarma@works

55HMG CoA Reductase

Inhibitors (Statins)

Statin Dose RangeLovastatin 20–80 mgPravastatin 20–40 mgFluvastatin 20–80 mgSimvastatin 20–80 mgAtorvastatin 10–80 mgRosuvastatin 5–20 mgCerivastatin 0.4–0.8 mg

Dr.Sarma@works

56

AtorvastatinAtorvastatin211 mg/dl*211 mg/dl*

SimvastatinSimvastatin219 mg/dl*219 mg/dl*

-60%

-50%

-40%

-30%

-20%

-10%

0%

Mea

n %

Cha

nge

from

Bas

e li n

eLDL-C Lowering - Statin Dose

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

Daily DoseDaily Dose

10 mg

20 mg

40 mg

80 mg16% with16% with3 Titrations3 Titrations

13%13%

38%

46%

51%54%

28%

35%

41%

Dr.Sarma@works

57

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

Dr.Sarma@works

58

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

Dr.Sarma@works

59



Ezetimibe

Cholesterol

NPC1L1

CholesterylEster ABCG5/G8

ACAT

Ezetimibe

XX

Dr.Sarma@works

60

Dual Inhibition

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

CMapoB48

LiverLiverLiverLiver

CM RemnantapoB48

VLDLapoB100

Ezetimibe

XX

LDLapoB100

XXStatinStatin

ColonColonColonColon

Dr.Sarma@works

61

Ezetimibe Efficacy (“10 + 10 = 80”)

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

Atorvastatin40 mg(n=66)

20 mg(n=60)

10 mg(n=60)

Me a

n %

Cha

n ge

in L

DL-C

f ro m

Bas

e li n

e

–53%

–37%–42%

–45%

–54%

P < 0.01P < 0.01

80 mg(n=62)

-60%

-50%

-40%

-30%

-20%

-10%

0%

Ezt + Ator10+10 mg

(n=65)

Dr.Sarma@works

62

Bile Acid Resins: Mechanism of Action

Net Effect - Net Effect - LDL-CLDL-CNet Effect - Net Effect - LDL-CLDL-C

Gall BladderGall Bladder

LDL ReceptorsLDL Receptors

VLDL and LDL removalVLDL and LDL removal

Cholesterol 7-Cholesterol 7- hydroxylase hydroxylase

Conversion of cholesterol to BAConversion of cholesterol to BA

BA SecretionBA Secretion

LiverLiver

BA ExcretionBA Excretion

Terminal IleumTerminal Ileum

Bile AcidBile Acid

Enterohepatic RecirculationEnterohepatic Recirculation

Reabsorption of Reabsorption of bile acidsbile acids

Dr.Sarma@works

63

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)

Dr.Sarma@works

64

Bile Acid Resins

Drug Dose Range

Cholestyramine 4–16 g

Colestipol 5–20 g

Colesevelam 2.6–3.8 g

Dr.Sarma@works

65

Treatment of ↓ HDLc

Low HDLcLow HDLcLow HDLcLow HDLc


Add on drug - FinofibrateAdd on drug - FinofibrateAdd on drug - FinofibrateAdd on drug - Finofibrate

Therapy of Choice : NiacinTherapy of Choice : NiacinTherapy of Choice : NiacinTherapy of Choice : Niacin


The CADI study [Coronary Artery Disease in Asian Indians]

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

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

Atherosclerosis , Rosemount , IL Oct 6-11 , 1991

120

86

100

80604020

0 14

95

5

Asian Indian males

Asian Indian females

% with < optimal level of HDL-C

% with an optimal HDL-C levels

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

Dr.Sarma@works

67

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

Dr.Sarma@works

68

Nicotinic Acid – Mechanism of Action

LiverLiver CirculationCirculationHDLHDL

Serum VLDL Serum VLDL results in reduced results in reduced lipolysis to LDL lipolysis to LDL

Serum LDLSerum LDL

VLDL

Decreases hepatic production of VLDL and of apo BDecreases hepatic production of VLDL and of apo B

VLDL VLDL secretionsecretion

Apo BApo B

HepatocyteHepatocyte Systemic CirculationSystemic Circulation

Mobilization of FFAMobilization of FFA

TG TG synthesissynthesis

VLDL

LDL

Dr.Sarma@works

69

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 NiaspanHDL-C with Niaspan®®

TG with NiaspanTG with Niaspan®®

TG with crystalline niacinTG with crystalline niacin

LDL-C with NiaspanLDL-C with Niaspan®®

LDL-C with crystalline niacinLDL-C with crystalline niacin

35%HDL-C with crystalline niacinHDL-C with crystalline niacin

Dr.Sarma@works

70

Nicotinic Acid Products availableProducts available

Immediate-release, 2–4 g/d, Sustained Release 3 g /dImmediate-release, 2–4 g/d, Sustained Release 3 g /d Extended-release (NiaspanExtended-release (Niaspan®®) 1–2 g/d) 1–2 g/d

Best agent to raise HDL-CBest agent to raise HDL-C Reduces coronary events Reduces coronary events Adverse effectsAdverse effects

Flushing, itching, headache (immediate-release, NiaspanFlushing, itching, headache (immediate-release, Niaspan®®)) Hepatotoxicity, GI (sustained-release)Hepatotoxicity, GI (sustained-release) Activation of peptic ulcerActivation of peptic ulcer Hyperglycemia and reduced insulin sensitivityHyperglycemia and reduced insulin sensitivity

ContraindicationsContraindications Active liver disease or unexplained LFT elevationsActive liver disease or unexplained LFT elevations Peptic ulcer diseasePeptic ulcer disease

Coronary heart disease and HDL-CFramingham Heart Study

Coronary heart disease and HDL-CFramingham Heart Study

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

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

The Physicians Health Study

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

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

*Men aged 50–70 Gordon, Castelli et al. Am J Med 1977; 62: 707–714Gordon, 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

Dr.Sarma@works

74

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

Dr.Sarma@works

75

Treatment of ↑ TG

High TGHigh TGHigh TGHigh TG


Add on drug – Statin, NiacinAdd on drug – Statin, NiacinAdd on drug – Statin, NiacinAdd on drug – Statin, Niacin

Therapy of Choice : FibrateTherapy of Choice : FibrateTherapy of Choice : FibrateTherapy of Choice : Fibrate


Dr.Sarma@works

76

Treatment Strategy

Fasting TG Level TG < 150

↑Fasting TG LevelNormal

< 2 RF

TG >150, No CHD

TG > 150, CHD +

TG > 500, CHD +/-

Diet Modify

Diet + Fibrate

2 or > RF

Diet + Fibrate + Niacin

Diet + Fibrate + Statin

Dr.Sarma@works

77

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

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

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

Dr.Sarma@works

79

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

Dr.Sarma@works

80

Fibric Acid Derivatives

Drug DoseClofibrate 1000 mg BIDBezafibrate 200 mg BIDGemfibrozil 600 mg BIDFenofibrate 200 mg ODFenofibrate micronized 160 mg OD

Dr.Sarma@works

81

Treatment of ↑ LDL + ↑ TG

CombinedCombinedCombinedCombined


Add on drug – Niacin, BARAdd on drug – Niacin, BARAdd on drug – Niacin, BARAdd on drug – Niacin, BAR

Therapy of Choice : Statin + FibrateTherapy of Choice : Statin + FibrateTherapy of Choice : Statin + FibrateTherapy of Choice : Statin + Fibrate


Dr.Sarma@works

82

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 +Simva +GemfibrozilGemfibrozil

––50%50%––39%39%

16%16%22%22%

––41%41%

––28%28%

Ator or Simva +Ator or Simva +FenofibrateFenofibrate

230230 332332

3838

191191166166

LDLLDLTGTG

HDLHDL

LDLLDL

TGTG

HDLHDL

Perc

ent C

hang

ePe

rcen

t Cha

nge

3434

Dr.Sarma@works

83

Statin + Fibrate – Precautions

Use statin alone for non-HDL-C goalsUse statin alone for non-HDL-C goals

Use fish oils or niacin rather than fibratesUse fish oils or niacin rather than fibrates

Keep the doses of the statin and fibrate lowKeep the doses of the statin and fibrate low

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

Avoid (or cautiously use) combo in renal impairmentAvoid (or cautiously use) combo in renal impairment

Teach the patient to recognize muscle symptomsTeach the patient to recognize muscle symptoms

Discontinue therapy if muscle symptoms are present Discontinue therapy if muscle symptoms are present and CK is >10 times the upper limit of normaland CK is >10 times the upper limit of normal

Dr.Sarma@works

84

Probucol

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

2. Third line drug – erratic 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

Dr.Sarma@works

85

The Three Canons

↑ LDL - STATIN↑ LDL - STATIN

↑ TG

- FI

BRAT

E

↑ TG

- FI

BRAT

E ↓ HDL - NIACIN

↓ HDL - NIACINDYSLIPIDEMIA

Dr.Sarma@works

86

Summary of Drug choice

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 LDLAtherogenecity 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, TGCirculation, 2000, 102: 716-721

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, TGCirculation, 2000, 102: 716-721

Dr.Sarma@works

88

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

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

Phenotype B or ALP

0

10

20

30

40

50

60

70

80

90

100

20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 500

Phenotype A

Phenotype B

% Cumulativefrequency

TG (mg/dL)

Cumulative Distribution of TG Levels Phenotypes A and B

Cumulative Distribution of TG Levels Phenotypes A and B

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

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

Phenotype A

Phenotype B

% Cumulativefrequency

HDL-C (mg/dL)

100

90

80

70

60

50

40

30

20

Cumulative Distribution of HDL levels Phenotypes A and B

Cumulative Distribution of HDL levels Phenotypes A and B

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

Metabolic Syndrome - Characteristics

HypertriglyceridemiaLow HDL-cholesterolElevated apolipoprote in BSmall, dense LDL particlesInflammatory profile

Insulin resistanceHyperinsulinem iaGlucose intoleranceImpaired fibrino lysisEndothelial dysfunction

These features can lead to type 2 diabetes,

hypertension and cardiovascular disease

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

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.

Dr.Sarma@works

95

Homocysteine

• 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

Dr.Sarma@works

96

Summary of Drug choice

Lipid abnormality type Advised Rx. Remarks

↑ Homocysteine Folic acid B6 + B12 helps

↑ 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

Dr.Sarma@works

97

Some Brand Names

Drug class Brand name

Atorvastatin TG-TOR, Storvas, Avastin, Atcor

Simvastatin Sim, Simvotin, Simcard, Simvas

Atorvastatin + Ezetimibe TG tor Z, Storvas Z,

Ezetimibe Ezedoc, Ezee, Ezet

Fenofibrate Lipicard, Fibrate, Finolip, Stanlip

Gemfibrozyl Lopid, Lipizyl, Normolip, Losterol

Niacin Niasyn, Nialip, Nicocin

Dr.Sarma@works

98

Atherosclerosis and IR and DM

HypertensionHypertension

ObesityObesity

HyperinsulinemiaHyperinsulinemia

DiabetesDiabetes

HypertriglyceridemiaHypertriglyceridemia

Small, dense LDLSmall, dense LDL

Low HDLLow HDL

HypercoagulabilityHypercoagulability

InsulinInsulinResistanceResistance

InsulinInsulinResistanceResistance AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis

Dr.Sarma@works

99

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

Dyslipidemia in IR and DM

All Diabetics must be given STATIN

Dr.Sarma@works

100

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

Dr.Sarma@works

101

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

Dr.Sarma@works

102

Who is to be blamed ??

We do not care at all to We soon end up having

Restrict diet, over eat CHO, sweet toothed Over weight and obesity

Eat more fruits, fiber, vegetables Atherosclerosis and AVD

Avoid fatty, crunchy, munchy tasty food Dyslipidemia and CHD

Avoid salty, savory, preserved food, NV Hypertension, CVA

Do the minimum required exercise Diabetes, IR, ↓ HDL, OA

Take enough milk and milk products, Ca Osteoporosis & fractures

Quit smoking and abstain from alcohol What not !

Control worry, anger, vengeance, jealousy Mental & physical illness

Where are we heading ? ?

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

20000 B.C. 2004

Hunting-gatheringsubsistence

High level ofphysical activity

Processedfoods

Animal fatsand glucidesDietary fibre¯

Sedentary life

Paleolithic sup. age Neolithic age 19th century 21st century

Thrifty genotype Susceptibility genotype

Technology has changed a lot in the way we live

But, we have not altered our life style

We have to pay the very heavy price !!

What could be prevented, we treat or leave

Dr.Sarma@works

105

Web Resources on Lipids

www.lipidsonline.org

www.hypertensiononline.org

www.ncbi.nlm.nih.gov

www.univ baylor.org

http://www.lipidsonline.org/

http://www.hypertensiononline.org/

http://www.ncbi.nlm.nih.gov/

http://www.univbaylore.org/

Dr.Sarma@works

106

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

Dr.Sarma@works

107

Wishing YOU all

A HAPPAY NEW YEAR

Dr.Sarma@works 1 Welcome to You All. Dr.Sarma@works 2 Dr.Sarma RVSN, M.D., M.Sc (Canada) Consultant in Medicine and Chest, President IMA – Tiruvallur.

Documents

thrombus slide

ed slide

sarma rvsn

gf atherosclerosis slide

ldl cholesterol

forms of avd slide

chd risk factors

renovascular disease