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)
Diet
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
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
Diabetes Atherosclerosis Intervention StudyDiabetes Atherosclerosis Intervention StudyDAISDAIS
Diabetes Atherosclerosis Intervention StudyDiabetes Atherosclerosis Intervention StudyDAISDAIS
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
De Lorgeril et al Circulation 1999;99:779
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
De Lorgeril et al Circulation 1999;99:779
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
A
B
Diabetes Atherosclerosis Intervention StudyDiabetes Atherosclerosis Intervention StudyDAISDAIS
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
Diabetes Atherosclerosis Intervention StudyDiabetes Atherosclerosis Intervention StudyDAISDAIS
Diabetes Atherosclerosis Intervention StudyDiabetes Atherosclerosis Intervention StudyDAISDAIS
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
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
End
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
Diet
Digestion