Lipids made simple

81
LIPIDS in primary care

Transcript of Lipids made simple

Page 1: Lipids made simple

LIPIDS in primary care

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• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion

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Lipoprotein metabolism

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The Lipids and Lipoproteins1. Ester. Cholesterol

(EC)2. Triglycerides (TG)

What are the important

components (two) of

lipids in the plasma ?

What are the other two

components in lipids in

their outer layer ?

1. Free Cholesterol (FC)2. Phospholipids (PL)

What are Apoproteins ? Why are they needed

in the lipid molecules ?

1. The outer protein coat is made of Apoproteins

2. To make lipids soluble and thus help transport

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ECTG

Apoprotein boat

1.Make the lipids soluble and transportable

2.Structural Integrity of the lipoprotein

3.Act as ligands for cell receptors4.Activate enzymes such as LPL, LCAT

as cofactors

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Cholesterol biosynthesis

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CORECHOLESTEROL

ESTERS

TRIGLYCERIDES

MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOL

INTEGRAL APOPROTEINS

PERIPHERAL APOPROTEINS

Structure of lipoprotein

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The Lipoprotein Particles

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Lipemic Turbid Serum

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The Atherogenic Particles

Apolipoprotein B

Non-HDL-CMeasurements

TG-rich lipoproteins

VLDL VLDLR IDL LDL SLDL

The smaller the particleThe greater is the danger

Lp(a)Chylo M

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Duodenum

Fat

CCK

Bile salts

Micelles

Enterocytes

ACAT

Lacteal Thoracic duct Systemic circulation

apo B-48

apo-Capo-E

Chylomicron

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Liver

Chylomicron

apo-B-48

apo-E

apo-C

Adipocyte

Chylomicron remnant

When TGs < 20% remaining, they loose apoC

apoE

VLDL

LDL-R Chylomicron remnant receptor

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Liver

apo-B-100

TGs <50%

TGs <30%

VLDL Remnant

IDL

TGs < 10%Loses apoE & apoC

LDL

LDL-R

apo-B-100

Cell wall Aldosterone

CortisolSex

hormones

apoB-100

VLDL

VLDL

LPL

Adipocyte &Myocyte

Remains attached to LPL

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Chylomicrons and VLDL

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• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion

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LDL

LDLEndothelium

Vessel LumenMonocyte

Macrophage

AdhesionMolecules

Havoc by LDL at Endothelium

Foam Cell

Intima

Modified LDLCytokines

Cell ProliferationMatrix Degradation

Growth FactorsMetalloproteinases

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

MCP-1

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Statin Evolution

1991 1993 1994 1995 1997 1999 2001 20032004

Pravastatin ApprovedSimvastatin Approved

NCEP(ATP II)

Atorvastatin Approved

Cervastatin Approved

NCEP(ATP III)

Cervastatin Withdrawn

Ezetimibe Approved

Rosuvastatin Approved

MARS4S

WOSCOPS

CAREPost CABG

LIPID –AFCAPS/TexCAPSMIRACL

FLORIDAHPS

PROSPER

ALLHAT

ASCOT

REVERSAL

CARDS

PROVE IT - TIME22AZZ

TNTIDEA

L

SEARCH

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PI=placebo; Rx=treatment

Shepherd J et al. N Engl J Med. 1995;333:1301-1307.4S Study Group. Lancet. 1995;345:1274-1275.Sacks FM et al. N Engl J Med. 1996;335:1001-1009.Downs JR et al. JAMA. 1998;279:1615-1622.Tonkin A. Presented at AHA Scientific Sessions, 1997.

Mean LDL-C level at follow-up (mg/dL)

Relation Between CHD Events and LDL-C in Recent Statin Trials

0

5

10

15

20

25

30

90 110 130 150 170 190 210

% withCHD event CARE-Rx

LIPID-Rx

4S-Rx

CARE-PILIPID-PI

4S-PI

2° Prevention

1° Prevention

WOSCOPS-PI

WOSCOPS-RxAFCAPS/TexCAPS-Rx

AFCAPS/TexCAPS-PI

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-20

-26

5

-31-33

-22-25

-35

8

-34

-42

-30

-20

-28

5

-24

-20

-9

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159)

N=number enrolled.

TC LDL-C

HDL-C

1o prevention

2o prevention

2o prevention

Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Recent Statin

TrialsNonfatal MI/CHD death

CHD death

All-cause mortality

%+

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Lipid Profile Report

PP Fasting

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Lipid profile report

• TC 200 mg/dl • HDL 40 mg/dl• TGL 150 mg/dl

• VLDL = 30 (TGL/5)• LDL =130 (TC-HDL-

VLDL)

• TC 200 mg/dl • HDL 40 mg/dl• TGL 450 mg/dl

• VLDL = 90 (TGL/5)• LDL =70(TC-HDL-

VLDL)

Non HDL

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NON HDL C=Total Cholesterol– HDL cholesterol

VLDL

IDL

LDL

VLDL

IDL

LDL

NONHDL

SMALL DENSE APO B

NON HDL GOAL: 30mg above LDL goal

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ATP III

• Obtain a fasting lipid profile • CHD risk factor • Major risk factors (ABC HF)• Target LDL• TLC

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LDL mass may underestimate atherogenic risk

Cholesterolbalance

100 mg/dL 100 mg/dL

Up to 70%more particles

Adapted from Otvos JD, et al. Am J Cardiol 2002; 90 (suppl):22i-29i

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• Increased susceptibility to oxidation

• Increased vascular permeability

• Decreased affinity for LDL receptor

• Association with insulin resistance syndrome

• Association with high TG and low HDL

Small Dense LDL and CHD: Potential Atherogenic Mechanisms

Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

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Statin Action

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Time Course of Statin Effects

* Time course establishedDays Years

LDL-C lowered*

Inflammationreduced

Vulnerableplaquesstabilized

Endothelialfunctionrestored

Ischemicepisodesreduced

Cardiac eventsreduced*

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Dual Inhibition

DuodenumDuodenum

JejunumJejunum

IleumIleum

CMapoB48

LiverLiver

CM RemnantapoB48

VLDLapoB100

Ezetimibe

X

LDLapoB100

XStatin

ColonColon38

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Rosuva

Simva

Atorva

10 mg

Adapted from Jones P.H. et al. Am J Cardiol 2003;92:152–160

20 40 80

Prava Not achieved with maximum licenced dose

Statin Dose Required to Achieve 45–50% Reduction

Fluva Not achieved with maximum licenced dose

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Jones PH, et al. Am J Cardiol. 2003;92:152–160.

-60%

-50%

-40%

-30%

-20%

-10%

0%

Mean

% C

han

ge in

LD

L-C

fro

m

Un

treate

d B

aselin

e V

alu

e Atorvastatin Rosuvastatin Simvastatin

14% with3 titrations

9% with2 titrations

18% with3 titrations

10 mg 20 mg 30 mg 40 mg

−28

−7−4−7

−46†

−6*−3*

−37

−6−5−3

The Initial Statin Dose is Important

The Initial Statin Dose is Important

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Molecular pathway

EARLYHIGH DOSE

Lipophylic statins better

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Additional sulphone binding site Arg568

Istvan and Deisenhofer Science 2001; 292:1160-1164

Rosuvastatin

Rosuvastatin: Additional binding site with HMG-CoA

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0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Fluvastatin (20, 40, 80 mg)

Rosuvastatin (10, 20, 40 mg)

Lovastatin (20, 40, 80 mg)

Atorvastatin (10, 20, 40, 80 mg)

Simvastatin (40, 80 mg)

Occu

rren

ce o

f A

LT >

3

×ULN

(%

)

Persistent elevation is elevation to >3 x ULN on 2 successive occasionsBrewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

ALT >3 × ULN: Frequency by LDL-C reduction

Liver effects - Benefit versus Risk

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Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Occu

rren

ce o

f C

K >

10 ×

ULN

(%

)

Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)

Rosuvastatin (10, 20, 40 mg)

Pravastatin (20, 40 mg)

Atorvastatin (10, 20, 40, 80 mg)

Simvastatin (40, 80 mg)

CK >10 x ULN: Frequency by LDL-C Reduction

Muscle effects - Benefit versus Risk

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CHD All Patients

High RiskPati

ents

Ach

ievin

g G

oal

(%)

Inadequate Achievement of NCEP ATP III Treatment Goals, Especially among

Patients at Highest Risk

70%

Adapted from Pearson TA et al. Arch Intern Med 2000;160;459-467.

Low Risk

Drug therapy included statins (fluvastatin, lovastatin, pravastatin, simvastatin), gemfibrozil, bile acid sequestrants, niacin, psyllium fiber, and combination drug therapy.

1,352 4,1371,924861

40%

18%

39%

n =

0%

20%

40%

60%

80%

100%

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34.9

24.8

29.6

19.4

0

10

20

30

40

Diabetes No Diabetes

ControlTreatmentc

Maj

or V

ascu

lar

Eve

nt R

ateb

, %

CVD Risk Higher Than Patients With No Diabetes on Placebo

Residual Risk

Diabetes No Diabetes

Residual Risk

CTT Collaborators. Lancet. 2008;371:117-125.

a4.3-year mean follow-up of 18 686 patients with diabetes; n = 71 370 patients with no diabetesbNonfatal MI, CHD death, stroke, or coronary revascularizationcEvent rate per 1 mmol/L (39 mg/dL) reduction in LDL-C

Statin Therapy Residual CVD Events

CTT Meta-Analysis of 14 Statin Trialsa

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• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion

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Bays H. Expert Rev Cardiovasc Ther 2004;2:89-105.

HL

TGRemnants

Smalldense LDL

HL

TG

Renal clearance

Smalldense HDL

TG

HL

Atherogenic Dyslipidemia

CETP

TG

CE

CETPCE

TG

LPL

TG

Apo E

TG

High

ApoCIII

Apo B

TGRL

TG

CE

TGpool

Adiposity High carbohydrate

diet Insulin resistance Genetic

predisposition

TGTG

CE

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30-D

ay R

isk

Dea

th,

MI,

Or

Rec

urre

nt A

SC

(%)

Role of Triglycerides: PROVE IT-TIMI* Trial1

• Elevated triglyceride level ≥200 mg/dL increases the risk of death, myocardial infarction or acute coronary syndrome

significantly

LDL-C <70 mg/dL,on statins

1. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.

On – Treatment (mg/dL)

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TGL/HDL RATIO

• BELOW 3.8 FOR ASIANS 3.0• GOOD USEFUL RATIO IN DIABETICS,

METABOLIC SYNDROME • ABNORMAL RATIO INDICATES

INCREASE IN SMALL DENSE LDL ALTHOUGH BLOOD LEVELS OF LDL IS NORMAL OR LOW

JACC 2005

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• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion

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LDL-C & HDL-C v/s CAD RiskFramingham Heart Study

Reprinted from Castelli WP. Can J Cardiol. 1988;4:5A–10A, with permission from Pulsus Group Inc.

0

1

2

3

220 160 100 mg/dL85

6545

25

HDL Chol

este

rol (

HDL-C)

LDL Cholesterol (LDL-C)

Coro

nary

Art

ery

Dis

ease

(

CA

D)

Rela

tive R

isk

mg/d

L

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Antioxidative Activity

AntithromboticActivity

ReverseCholesterolTransportCellular

CholesterolEfflux

AntiapoptoticActivity

Anti-inflammatoryActivity

HDL-CAnti-infectious

Activity

Adapted from Chapman MJ et al. Curr Med Res Opin. 2004,20:1253-1268, with permission from LibraPharm, Ltd.Assmann G et al. Annu Rev Med. 2003,54:321-341.

EndothelialRepair

VasodilatoryActivity

Antiatherogenic Actions of HDL-C

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Relationship Between Changes in

LDL-C and HDL-C Levels and CHD Risk

Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670. 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

1% decreasein LDL-C reduces CHD risk by 1%

1% increasein HDL-C reduces CHD risk by 3%

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Nicotinic Acid – Mechanism of Action

Liver CirculationHDL

Serum VLDL results in reduced lipolysis to LDL

Serum LDL

VLDL

Decreases hepatic production of VLDL and of apo B

VLDL secretion

Apo B

Hepatocyte Systemic Circulation

Mobilization of FFA

TG synthesis

VLDL

LDL

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Lipid Effects of Niacin Extended-Release (ER)

Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U.

• Lipid effects

– Most potent agent for HDL: 20%+; nonlinear– Favorable effects on LDL-particle density– LDL (linear), TG, and Lp(a)

• Tolerability with concomitant statin therapy

– No change in rate of liver adverse effects or myositis versus statin monotherapy

302010

0-10-20-30-40-50

mg500 1000 1500 2000 2500 3000

Ch

an

ge f

rom

Base

line

(%)

-8-13

-22 -21-16

293024

2116

10

-21

-32

-44-39

-14

-5

-26

-3

-12

-30-25

-17

HDL-C

LDL-C

Lp(a)

TG

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0%

20%

40%

60%

80%

100%

4 wk 8 wk 12 wk 24 wk 1 y

Pe

rce

nt

Us

ers

Average Daily Dose of ER Niacin Prescription Refills at Fixed Time Intervals Niaspan discontinuation rate high, adherence rate low, dose less optimal. Only 47% of all ER niacin users reached recommended maintenance dose of 1000 mg or higher, and only 77% reached the dose of 2000 mg during follow-up. Clinical evidence showed that nonadherence for medication leads to the prevalence of the disease and discontinuation from medication increases patient mortality risk.

1. Retrospective cohort study using administrative claims data from 2000 to 2003 Ingenix Lab/Rx Database™. Kamal-Bahl et al. Abstract presented at AHA 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, Washington, D.C., May, 2006. 2. Ho PM, et al. Arch Intern Med. 2006;466:1836–1841. 3. Ho PM et al. Arch Intern Med. 2006;166:1842–1847.

N=14,386 N=6,349 N=5,277 N=5,402 N=2,104

>1500 mg

1001-1500 mg

751-1000 mg

501-750 mg

≤500 mg

Niacin-Induced Flushing Limits Niacin Utilization

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AIM-HIGH

3300 patients

Primary End PointComposite of CHD death, nonfatal MI, ischemic stroke, or hospitalization for high-risk ACS with objective evidence of ischemia

Key Secondary End PointsComposite of CHD death, nonfatal MI, or ischemic stroke

4 year follow-up

Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes

ClinicalTrials.gov Identifier: NCT00120289

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DUAL PATHOGEN

ATHEROGENIC

THROMBOGENIC

RISK:2-4 FOLDWTH LOW HDL:8 FOLDWITH HIGH LDL:12 FOLDALL THREE:25 FOLD

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RESIDUAL RISK DUE TO

• LOW HDL• HIGH TRIGLYCERIDES• SMALL DENSE LDL• NON HDL CHOLESTEROL• Hs CRP• LIPOPROTEIN (a)

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*P<0.002 RSV 20 mg vs ATV 20, 40 & 80 mg; RSV 40 mg vs ATV 40 & 80 mg

Jones P.H. et al. Am J Cardiol 2003;92:152–160

0

2

4

6

8

10

12

Mean

ch

an

ge in

HD

L-C

from

baselin

e (

%)

7.7%

9.6%*

Rosuvastatin*

10 20 40 80

Dose, mg (log scale)

3.2%

5.6%

Pravastatin6.8%

Simvastatin

5.3%

2.1% Atorvastatin

5.7%

Rosuvastatin achieves significantly greater increase

in HDL-C

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RESIDUAL RISKTHE ISSUES

• Whether treating residual risk is really needed when LDL goal is achieved ?

• How to treat it?• Is there evidence that treating

residual risk decreases clinical events?

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4 major statin benefit groups were identified for whom the ASCVD risk reduction clearly outweighs the risk of adverse events.

1) with clinical ASCVD, 2) primary elevations of LDL–C >190 mg/dL, 3) diabetes aged 40 to 75 years with LDL– C 70

to189 mg/dL and without clinical ASCVD, or 4) without clinical ASCVD or diabetes with LDL–C

70 to189 mg/dL and estimated 10-year ASCVD risk >7.5%.

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• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion

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Major recommendations for statin therapy for ASCVD prevention

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Major recommendations for statin therapy for ASCVD prevention (Conti.... from prev.

page)

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Initiating statin therapy in individuals with clinical ASCVD

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Initiating statin therapy in individuals without clinical ASCVD

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Initiating statin therapy in individuals without clinical ASCVD (Conti.... from prev.

page)

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Statin Therapy: Monitoring therapeutic response and adherence

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Guidelines that aren’t

implemented never workNow, we have an unparalleled

opportunity to prevent ASCVD

– but, only if we act !!

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