Approach to the Management of Hypertriglyceridemia

Approach to theManagement of

Hypertriglyceridemia

Timothy A. Denton, M.D.Attending Cardiologist

High Desert Heart InstituteVictorville, CA

Outline

•Lipids / Triglyceride metabolism•Etiology of hypertriglyceridemia•Therapy of hypertriglyceridemia•Special considerations

Can you identify these?

VLDL

B100

CI CIICII CIII

E

IDL B100

E

LDL B100

Chylomicrons

B100

CICII

CIII

E

AI

AII

AIV

B48

Remnants

B48

E

HDL2

AI

AII

AI

AII

HDL3

HDL1

AI

AII

VLDL

Chylomicrons

Remnants

HDL2IDL

LDL

HDL1

HDL3

50-90 A

90-120 A

120-180 A

180-280 A

250-350 A

300-800 A

800-5000 A

>300 A

Egg McMuffin

Calories 290Calories from fat 110Total fat 12 gSaturated fat 4.5 gCholesterol 235 mgSodium 790 mgCarbohydrates 27gProtein 17g

http://www.mcdonalds.com/countries/usa/

Chylomycron Production

Intestinal Brush Border

Triglyceride Concentration over Time

Ng et al. Arterio Thromb Vasc Biol 1995;15:2157-2164

C = 8 - 24

Fatty Acids

Lipids

HO

O

Triglycerides

O

O

O

O

O

O

Phospholipids

O

O

O

O

O

PGO

O

HO

Cholesterol

O

Cholesterol Ester

Fatty Acid

OHC

O

+H O H

C

O

Fatty Acids

• Number of carbons are multiples of 2 (from Acetyl-CoA)• Length of FA

Short chain = 2-6 carbonsMedium chain = 8-14 carbonsLong chain = 16 +

• Saturated FA contain no double bonds• Monounsaturated FA contain 1 double bond• Polyunsaturated FA (PUFA) contain 2 or more double bonds• Many, many other types of FA

Fatty Acids

C

H

H

C

H

H

C

H

C

H

C

H

H

C

H

Hcis

trans C

H

H

C

H

H

C

H

C C

H

H

C

H

HH

C

H

H

C

H

H

C

HH

CH

H CH

H

C

Cis is GOOD

C

H

H

C

H

H

C

H

C C

H

H

C

H

HH

Trans is BAD

PUFA (polyunsaturated fatty acid) Nomenclature

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Common name - -Linoleic acidSystematic name - all cis-9,12-octadecadienoic acidSystematic name - cis-9, cis-12-octadecadienoic acidChemist’s name - 18:2 (9Z, 12Z) (Z=cis, E=trans)Chemist’s name - 18:2 9,12 (assume cis, indicate trans)Nutritionist’s name #1 - 18:2 (n-6)Nutritionist’s name #2 - 18:2 -6

HO

O

18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

REALLY, REALLY Essential Fatty Acids

HO

O

Linoleic acid (18:2, n-6)

HO

O

-Linolenic acid (18:3, n-3)

Corn oilCotton seed oilLinseed oil (flax)Rapeseed (canola) oilSoya oilWalnut oil, walnutsPeanutsBeefSpinach

Fish oilseicosadocosa

Sardines, Salmon,Mackerel, Cod,Halibut, Herring,Trout, Tuna,Haddock

Lipid Metabolism

Gut

LIPOPROTEINLIPASE

Fatty acids

Chylomicronremnant

Liver

Chylomicron

VLDL

IDL

LDL

Whatyou

make

Whatyoueat

1,000 mg/day 300 mg/day

Bile

Lipemia

Apo B-48

Chylomicron Metabolism

Apo A-1

Apo C-II

Apo A-IV

Gut

Apo E

Apo C-III

LIPOPROTEINLIPASE

Fatty acidsApo A-1, A-IV

Apo C-II, C-III

Chylomicronremnant

= cholesterol

= triglyceride

= phospholipid

Liver

= cholesterol ester

Fatty Acid Transport

Triglyceride-richlipoprotein

Lipoproteinlipase

ApoC-II

Fatty acids

Triglyceridesynthesis

lipase

Triglyceridestorage

Energy

FATTY ACID-ALBUMIN COMPLEXES

Liver

Adipose tissue

Muscle

Fattyacids

LDL and IDL

Metabolism of VLDLApo B-100

Apo E

NascentVLDL

Mature VLDL

VLDLRemnant

LDL

Liver LIPOPROTEINLIPASE

HDLCholesterol esters

Apo E

Apo EApo C-II,C-III

PhospholipidsFattyacidsHDL

Apo C-II, C-III

Apo C-III

Apo C-II

Fibr

ates

Etiology• Genetic

Familial dysbetalipoproteinemiaFamilial combined hyperlipoproteinemiaFamilial hypertriglyceridemia (unknown)LPL deficiency / inhibitionApo C-II deficiency (LPL activator)Apo E defects / Apo E-2

• AcquiredDietAlcoholUremiaPregnancyDrug useHypothyroidism

Type LP Chol TG Athero %I Chylo + ++++ - <1IIa LDL ++ + +++ 10IIb LDL+VLDL ++ ++ +++ 40III IDL ++ +++ +++ <1IV VLDL + ++ + 45V Chylo + VLDL + ++++ + 5

Fredrickson Classification

LDL Cholesterol Goals and Cutpoints for Therapeutic LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC)Lifestyle Changes (TLC)

and Drug Therapy in Different Risk Categoriesand Drug Therapy in Different Risk Categories

LDL Cholesterol Goals and Cutpoints for Therapeutic LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC)Lifestyle Changes (TLC)

and Drug Therapy in Different Risk Categoriesand Drug Therapy in Different Risk Categories

190 190 (160–189: LDL-(160–189: LDL-

lowering drug optional)lowering drug optional)160160<160<1600–1 Risk Factor0–1 Risk Factor

10-year risk 10–20%: 10-year risk 10–20%: 130130

10-year risk <10%: 10-year risk <10%: 160 160

130130<130<1302+ Risk Factors 2+ Risk Factors

(10-year risk (10-year risk 20%)20%)

130 130 (100–129: drug (100–129: drug

optional)optional)100100<100<100

CHD or CHD Risk CHD or CHD Risk EquivalentsEquivalents

(10-year risk >20%)(10-year risk >20%)

LDL Level at Which LDL Level at Which to Considerto Consider

Drug Therapy Drug Therapy (mg/dL)(mg/dL)

LDL Level at Which to LDL Level at Which to Initiate Therapeutic Initiate Therapeutic Lifestyle Changes Lifestyle Changes

(TLC) (mg/dL)(TLC) (mg/dL)LDL GoalLDL Goal(mg/dL)(mg/dL)Risk CategoryRisk Category

Approach to the treatment ofHypertriglyceridemia

• Elevated TG’s>200 mg/dl

• “Abdominal” TG’s>500-1000 mg/dl

Therapy of Hypertriglyceridemia

• Underlying cause• Diet• Drugs• Plasmapheresis• Special considerations

Underlying Cause

• EtOH• DM• Obesity• HIV drugs

Underlying Cause

Central Obesity Contributes to Insulin Resistance

Abdominal fat:high rate of FA turnoverhigh rate of lipolysis

Classic Diabetic Lipid Pattern

• Low HDL• High LDL• High TG’s

HIV Drugs

• HIV itself• Protease inhibitors• Unclear etiology• High TG’s (800-3000 mg/dl)• Low HDL (as low as 1 mg/dl)• High LDL (300-800 mg/dl)

Ornish D, et al. Lancet 1990;336:129

Lifestyle Heart Trial

Changes in Fat Intake

31.5

6.8

30.1 29.5

0

5

10

15

20

25

30

35

40

45

50

Baseline 1 year

Die

tary

Per

cen

t F

at

Ornish D, et al. Lancet 1990;336:129

Lifestyle Heart Trial

Change in Serum Lipids(Intervention Group)

222

168

148

93

38 37

90110

0

50

100

150

200

250

Baseline 1 year

Die

tary

Per

cent

Fat

TCholLDLHDLTG

Dietary Goals

• NOT total fat reduction

• Total fat 10-20%

Partial Ileal Bypass

POSCH --Program On Surgical Control of Hyperlipidemias

-37.7

4.3

19.8

-50

-40

-30

-20

-10

0

10

20

LDL HDL TG

Per

cent

Cha

nge

Arch Int Med 1998;158:1253

Drugs

• Statins• Niacin• Fibrates• Fish oil

Statins

Jones et al. Am J Cardiol2003;92:152

6

-30

-13

6.8

-45.8

-18.2

2.1

-51.1

-28.2

9.6

-55

-26.1

-60

-50

-40

-30

-20

-10

0

10

20

HDL LDL TG

Prava Simva Atorv Rosuva

NiacinNicotinic acid

Niacin(Vit B3)

N

O

HO

N

O

NH2

Nicotinamide(no antilipemic activity)

Niacin Forms

Generic Trade Dose TG effect LDL effect Niacin OTC 0.25-6g/day -35-55% -30%

Slo-Niacin (Polygel)

OTC 0.25-6g/day “ -30%

Niacin-inositol No-Flush Niacin

3-7 tabs/day (625 mg)

“ -19.1%

Long-acting Niacin

Niaspan 3-7 tabs/day (625 mg)

“ -19.1%

Niacin Onset of Action

Apo B PathwayApo B-100

Apo E

NascentVLDL

Mature VLDL

VLDLRemnant

LDL

Liver LIPOPROTEINLIPASE

HDLCholesterol esters

Apo E

Apo EApo C-II,C-III

PhospholipidsFattyacidsHDL

Apo C-II, C-III

Apo C-III

Apo C-II

Niacin

Niacin

Fibrates

Drug Dosing Availability Clofibrate 600 bid YES Gemfibrozil 300 bid YES Fenofibrate 54, (107), 160 qd YES Bezafibrate 3x/day NO

Effect of Fibrates on Lipid Levels

VA-HIT NEJM 1999;341:410

• Increased Lipoprotein lipase activity• Increased liver uptake of FA, decreased TG production• Increased LDL affinity for receptor• Lower exchange between LDL and VLDL• Increased HDL production• PPARs

Effect of Fibrates on Lipid Levels

0

6

-31

-50

-40

-30

-20

-10

0

10

20

LDL HDL TG

Per

cent

Cha

nge

VA-HIT NEJM 1999;341:410

Effect of FenoFibrate on Lipid Levels

-19

11

-28.9

-23

9.8

-23.5

-17

14.6

-35.9

-50

-40

-30

-20

-10

0

10

20

LDL HDL TG

Per

cent

Cha

nge

MeanTg<150Tg>150

LDL Profile of FenofibrateLDL Profile of Fenofibrate LDL Profile of FenofibrateLDL Profile of Fenofibrate

-60%

-40%

-20%

0%

20%

40%

60%

Caslake; Arterioscler Thromb 1993:13;702-11

% C

hang

e

TC LDL-C LDL Receptor Uptake

Large Buoyant

LDL

Small Dense LDL

BIPBezafibrate Infarction Prevention Study

Circulation 2000;102:21-27

Endpoint Bezafibrate(%)

Placebo(%)

P

Non-fatal MI 9.7 11.2 0.18

Fatal MI 1.2 1.1 0.87

SCD 2.8 2.8 0.98

UA 4.9 5.3 0.61

CABG 9.3 10.2 0.41

PTCA 5.9 5.7 0.84

All endpoints 33.7 36.3 0.14

Cardiac mortality 6.1 5.7 0.61

Noncardiac mortality 4.3 4.2 0.87

CVA 4.6 5.0 0.66

Diabetes Atherosclerosis Intervention StudyDiabetes Atherosclerosis Intervention StudyDAISDAIS


1.1. DM II, DM II, with and without coronary interventionwith and without coronary intervention

2.2. Randomized, prospectiveRandomized, prospectivefenofibrate vs placebofenofibrate vs placebo

3.3. 418 randomized418 randomized4.4. Follow-up - 39.6 monthsFollow-up - 39.6 months5.5. End-pointsEnd-points

minimum lumen diameterminimum lumen diametermean segment diametermean segment diametermean % stenosismean % stenosis



3.65

-0.1

0.08

2.11

-0.06 -0.06

-2.0

-1.0

0.0

1.0

2.0

3.0

4.0

%Stenosis MinDiam MeanDiam

PlaceboFenofibrate

P=0.02

P=0.03 P=0.17

FenofibrateFenofibrate Adverse Events Adverse Events FenofibrateFenofibrate Adverse Events Adverse Events

Generally well toleratedGenerally well tolerated Most frequent discontinuation - rash (6% vs 2%)Most frequent discontinuation - rash (6% vs 2%) Other events: pruritis, constipation, diarrheaOther events: pruritis, constipation, diarrhea G.I. Upset 2% ( less than placebo)G.I. Upset 2% ( less than placebo) LFTs elevations 6.3% vs 2.1% for placeboLFTs elevations 6.3% vs 2.1% for placebo Increased warfarin levels (monitor INR)Increased warfarin levels (monitor INR)

PPARs are theCENTER of the UNIVERSE

Peroxisome Proliferator Activated Receptor

PPARα -- FibratesPPARγ -- Thiazolidinediones

PPARα Stimulation:

1. Reduces production of Apo CIII (inhibitor of lipolysis)

2. Activates Lipoprotein Lipase

3. Fall in TG levels

4. Switch from small dense to large “fluffy” LDL

5. Increases synthesis of Apo AI and AII

Fish Oil

• n-3 PUFA’s• Epidemiologic data on survival• GISSI-Prevenzione• Effects on Triglycerides

Fish Oil

• 9 patients• 6 weeks

1 g/d N-3 PUFA1 U tocopherol/d

• 6 weeks5 g/d fish oil

• Slower VLDL and LDL oxidation

Hau et al. Arterio Thromb Vasc Biol 1996;16:1197

-54 -56

-40

23

-60

-50

-40

-30

-20

-10

0

10

20

30

TG VLDL TG VLDL-C LDL

Fish Oil vs Gemfibrozil

29.7

11.0

-37.1

33.6

17.1

-40.4

-50

-40

-30

-20

-10

0

10

20

30

40

LDL HDL TG

FO Gemfib

Gemfibrozil 1,200 mg/dFish oil 4g/day

Stalenhoef et al Atherosclerosis 2000;153:129

n-3 PUFA’s and SCD

Albert et al NEJM 2002;346:1113

GISSI-Prevenzione

GISSI group, Lancet 1999;354:447

Mediterranian Diet

J. THOMSON "Chart of the Mediterranean Sea" Edin.18I7

Lyon Heart Trial

De Lorgeril et al Circulation 1999;99:779

•First MI•Randomized•Mediterranian vs Prudent•5 year trial stopped early

• <35% energy as fat• <10% energy saturated fat• <4% energy as linoleic acid• >0.6% of energy as alpha-linolenic (18:3 or n-3)

• Eat more bread• Eat more fish, less meat• Eat more vegetables• Must have fruit every day• All butter and margarine replaced with olive oil and canola oil

Lyon Heart Trial


Survival with:No MI

Survival with:No MIAnginaCHFCVAPEPeriph embol

Survival with:No MIAnginaCHFCVAPEPeriph embolStable anginaPTCA, CABGRestenosis

Control(n=204)

Intervention(n=219)

LDL 4.23 mmol/L163.6 mg/dL

4.17 mmol/L161.3 mg/dL

Lyon Heart Trial


Differences in LDL-C

Plasmapheresis

•Apheresis = Pheresis = Hemapheresis

•Apheresis -- (Latin, Greek -- aphairesis)to take out, take away, snatch, detach,separation, or abstract.

Combination Therapy

• Statin + niacin• Statin + fibrate• Statin + ezetimibe• Statin + resin

When in doubt, drop the statin to 20% of maximum dose,Add second drug

Titrate up while watching symptoms and LFT’s

Combination Therapy

2. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination.

Caution should be used when prescribing other lipid-lowering drugs (other fibrates or lipid-lowering doses (1 g/day) of niacin) with simvastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of simvastatin with fibrates or niacin should be carefully weighed against the potential risks of these combinations. Addition of fibrates or niacin to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained.

Zocor Package Insert

Combination Therapy

Crestor Package Insert

Fenofibrate: Coadministration of fenofibrate (67 mg three times daily) with rosuvastatin (10 mg) resulted in no significant changes in plasma concentrations of rosuvastatin or fenofibrate (see PRECAUTIONS, Drug Interactions, and WARNINGS, Myopathy/Rhabdomyolysis).

Gemfibrozil: Coadministration of gemfibrozil (600 mg twice daily for 7 days) with rosuvastatin (80 mg) resulted in a 90% and 120% increase for AUC and Cmax of rosuvastatin, respectively. This increase is considered to be clinically significant (see PRECAUTIONS, Drug Interactions, WARNINGS, Myopathy/Rhabdomyolysis, DOSAGE ANDADMINISTRATION).

Special Considerations

Central Obesity Contributes to Insulin Resistance

Abdominal fat:high rate of FA turnoverhigh rate of lipolysis

Diabetes and Lipids

• Elevated LDL• Elevated TG’s• Low HDL

LDL Sizing

• Ultracentrifugation• NMR• Gel elecrophoresis



1.1. DM II, DM II, with and without coronary interventionwith and without coronary intervention

2.2. Randomized, prospectiveRandomized, prospectivefenofibrate vs placebofenofibrate vs placebo

3.3. 418 randomized418 randomized4.4. Follow-up - 39.6 monthsFollow-up - 39.6 months5.5. End-pointsEnd-points

minimum lumen diameterminimum lumen diametermean segment diametermean segment diametermean % stenosismean % stenosis



Variable All (n=405)

Fenofibrate (n=198)

Placebo (n=207)

LDL size + LDL 0.039* 0.073* 0.008 LDL size + apoB

0.041* 0.078* 0.008

LDL size + HDL 0.026** 0.041** 0.016 LDL size + TG 0.027** 0.056** 0.007 LDL size + LDL + apoB + HDL + TG

0.044** 0.082** 0.021

* = P < 0.001 ** = P < 0.05

Change in Percentage Diameter Stenosis

Effect of Exercise on Lipids

Kokkinos Arch Int Med 1995:155:415

2906 menage 30-64 yearsexercise treadmill test to exhaustionclassified into 6 groups based on

average miles run per week

Effect of Exercise on Lipids

Kokkinos Arch Int Med 1995:155:415

LDL, TG, HDL versus miles per week

40

45

50

55

60

0-2 mi 3-6 mi 7-10 mi 11-14 mi 15-20 mi 21-60 mi

Miles Run per Week

HD

L m

g%

0

20

40

60

80

100

120

140

LD

L m

g%

Y2

HDLLDLTG

Trans-Fatty Acids

Lichtenstein NEJM 1999;340:1933

Summary

• Elevated TG’s are a risk factoratherosclerosispancreatitis

• Treat underlying cause• Use fibrates early• Use in combination carefully

Hypertriglyceridemia

• Familial chylomicronemiadeficiency or inhibitor of LPL or activator Apo C-IIeruptive xanthomas, abdominal paindiet Rx -- short-chain fatty acids

• Dysbetaliproproteinemiahomozygous for Apo E-2high IDL -- chylo and VLDL remnants accumulatediet therapy

• Familial endogenous hypertriglyceridemia• Familial combined hyperlipidemia

Digestion

Approach to the Management of Hypertriglyceridemia

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