Transcript No Slide Title

Approach to the
Management of
Hypertriglyceridemia
Timothy A. Denton, M.D.
Attending Cardiologist
High Desert Heart Institute
Victorville, CA
Outline
•Lipids / Triglyceride metabolism
•Etiology of hypertriglyceridemia
•Therapy of hypertriglyceridemia
•Special considerations
Can you identify these?
Chylomicrons
VLDL
E
E
B100
B100
AI
HDL1
AII
AI
AIV
AII
CI
CII CIII
B48
IDL
CI
CII
HDL2
B100
AI
CIII
AII
E
Remnants
E
HDL3
LDL
B100
AI
B48
AII
Chylomicrons
800-5000 A
VLDL
HDL1
300-800 A
IDL
120-180 A
HDL2
250-350 A
90-120 A
LDL
180-280 A
HDL3
Remnants
>300 A
50-90 A
Egg McMuffin
Calories
Calories from fat
Total fat
Saturated fat
Cholesterol
Sodium
Carbohydrates
Protein
290
110
12 g
4.5 g
235 mg
790 mg
27g
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
Lipids
C = 8 - 24
Fatty Acids
HO
O
O
O
Triglycerides
O
O
O
O
O
G
P
O
O
Phospholipids
O
O
O
O
Fatty Acid
Cholesterol
O
C OH
HO
Cholesterol Ester
O
C O
+
HOH
Fatty Acids
• Number of carbons are multiples of 2 (from Acetyl-CoA)
• Length of FA
Short chain = 2-6 carbons
Medium chain = 8-14 carbons
Long 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
cis
trans
H H
C C C C
H H
C C
H H
C C C
H H H H H H
H H H
Cis is GOOD
H H H
H H
C C C C C C
H H
C C C
H H H
H H H
Trans is BAD
H H
PUFA (polyunsaturated fatty acid)
Nomenclature
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18
O   

HO
18 17 16 15 14 13 12 11 10
9
8
7
 

6
4
5
3
2
1
Common name
- -Linoleic acid
Systematic name
- all cis-9,12-octadecadienoic acid
Systematic name
- cis-9, cis-12-octadecadienoic acid
Chemist’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
REALLY, REALLY Essential Fatty Acids
O
HO
Linoleic acid (18:2, n-6)
O
Corn oil
Cotton seed oil
Linseed oil (flax)
Rapeseed (canola) oil
Soya oil
Walnut oil, walnuts
Peanuts
Beef
Spinach
HO
Fish oils
-Linolenic acid (18:3, n-3)
eicosa
docosa
Sardines, Salmon,
Mackerel, Cod,
Halibut, Herring,
Trout, Tuna,
Haddock
Lipid Metabolism
Chylomicron
VLDL
Gut
IDL
What
you
make
Liver
What
you
eat
LIPOPROTEIN
LIPASE
Fatty acids
Chylomicron
remnant
Bile
LDL
1,000 mg/day
300 mg/day
Lipemia
Chylomicron Metabolism
Apo A-1
Apo B-48
Apo A-IV
= cholesterol
= phospholipid
= cholesterol ester
Apo C-III
Apo C-II
Gut
LIPOPROTEIN
LIPASE
Apo E
Fatty acids
Apo A-1, A-IV
Apo C-II, C-III
Liver
Chylomicron
remnant
= triglyceride
Fatty Acid Transport
Triglyceride-rich
lipoprotein
Triglyceride
synthesis
Liver
Apo
C-II
Fatty
acids
Fatty acids
FATTY
ACID-ALBUMIN COMPLEXES
Adipose tissue
lipase
Triglyceride
storage
Lipoprotein
lipase
Energy
Muscle
LDL and IDL
Metabolism of VLDL
Apo B-100
HDL
Nascent
VLDL
Mature VLDL
Apo E
Apo C-II
Liver
LIPOPROTEIN
LIPASE
Apo C-III
LDL
VLDL
Remnant
Etiology
• Genetic
Familial dysbetalipoproteinemia
Familial combined hyperlipoproteinemia
Familial hypertriglyceridemia (unknown)
LPL deficiency / inhibition
Apo C-II deficiency (LPL activator)
Apo E defects / Apo E-2
• Acquired
Diet
Alcohol
Uremia
Pregnancy
Drug use
Hypothyroidism
Fredrickson Classification
Type
I
IIa
IIb
III
IV
V
LP
Chylo
LDL
LDL+VLDL
IDL
VLDL
Chylo + VLDL
Chol TG
+
++++
++
+
++
++
++
+++
+
++
+
++++
Athero
+++
+++
+++
+
+
%
<1
10
40
<1
45
5
LDL Cholesterol Goals and Cutpoints for Therapeutic
Lifestyle Changes (TLC)
and Drug Therapy in Different Risk Categories
Risk Category
CHD or CHD Risk
Equivalents
(10-year risk >20%)
2+ Risk Factors
(10-year risk 20%)
0–1 Risk Factor
LDL Goal
(mg/dL)
<100
LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes
(TLC) (mg/dL)
LDL Level at Which
to Consider
Drug Therapy
(mg/dL)
100
130
(100–129: drug
optional)
10-year risk 10–20%:
130
<130
130
10-year risk <10%:
160
<160
160
190
(160–189: LDLlowering drug optional)
Approach to the treatment of
Hypertriglyceridemia
• 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 turnover
high 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
Lifestyle Heart Trial
Changes in Fat Intake
Dietary Percent Fat
50
45
40
35
31.5
30.1
29.5
30
25
20
15
10
5
6.8
0
Baseline
1 year
Ornish D, et al. Lancet 1990;336:129
Lifestyle Heart Trial
Dietary Percent Fat
250
Change in Serum Lipids
(Intervention Group)
222
200
168
150
148
110
90
100
50
38
93
TChol
LDL
HDL
TG
37
0
Baseline
1 year
Ornish D, et al. Lancet 1990;336:129
Dietary Goals
• NOT total fat reduction
• Total fat 10-20%
Partial Ileal Bypass
POSCH -Program On Surgical Control of Hyperlipidemias
19.8
20
Percent Change
10
4.3
0
LDL
HDL
TG
-10
-20
-30
-40
-37.7
-50
Arch Int Med 1998;158:1253
Drugs
• Statins
• Niacin
• Fibrates
• Fish oil
Statins
20
10
6
9.6
6.8
2.1
Prava Simva Atorv Rosuva
0
-10
HDL
LDL
TG
-13
-20
-30
-18.2
-28.2-26.1
-30
-40
-50
-60
-45.8
-51.1
-55
Jones et al. Am J Cardiol2003;92:152
Niacin
Nicotinic acid
Niacin
(Vit B3)
Nicotinamide
(no antilipemic activity)
O
O
HO
NH2
N
N
Niacin Forms
Generic
Niacin
Slo-Niacin
(Polygel)
Niacin-inositol
Long-acting
Niacin
Trade
OTC
OTC
Dose
0.25-6g/day
0.25-6g/day
TG effect
-35-55%
“
LDL effect
-30%
-30%
No-Flush
Niacin
Niaspan
3-7 tabs/day
(625 mg)
3-7 tabs/day
(625 mg)
“
-19.1%
“
-19.1%
Niacin Onset of Action
Apo B Pathway
Apo B-100
HDL
Nascent
VLDL
Mature VLDL
Apo E
Apo C-II
Niacin
Liver
LIPOPROTEIN
LIPASE
Apo C-III
LDL
VLDL
Remnant
Fibrates
Drug
Clofibrate
Gemfibrozil
Fenofibrate
Bezafibrate
Dosing
600 bid
300 bid
54, (107), 160 qd
3x/day
Availability
YES
YES
YES
NO
Effect of Fibrates on Lipid Levels
• 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
VA-HIT NEJM 1999;341:410
Effect of Fibrates on Lipid Levels
20
10
6
Percent Change
0
0
LDL
HDL
TG
-10
-20
-30
-31
-40
-50
VA-HIT NEJM 1999;341:410
Effect of FenoFibrate on Lipid Levels
20
14.6
11
9.8
Percent Change
10
0
LDL
HDL
TG
Mean
Tg<150
Tg>150
-10
-20
-17
-19
-23
-30
-40
-50
-23.5
-28.9
-35.9
LDL Profile of Fenofibrate
60%
40%
20%
0%
-20%
-40%
-60%
TC
LDL-C
LDL
Receptor
Uptake
Caslake;
Large
Buoyant
LDL
Small
Dense
LDL
Arterioscler Thromb 1993:13;702-11
BIP
Bezafibrate Infarction Prevention Study
Endpoint
Bezafibrate
(%)
9.7
Placebo
(%)
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
Non-fatal MI
P
Circulation 2000;102:21-27
Diabetes Atherosclerosis Intervention Study
DAIS
1. DM II,
2.
3.
4.
5.
with and without coronary intervention
Randomized, prospective
fenofibrate vs placebo
418 randomized
Follow-up - 39.6 months
End-points
minimum lumen diameter
mean segment diameter
mean % stenosis
Diabetes Atherosclerosis Intervention Study
DAIS
4.0
P=0.02
3.0
2.0
3.65
P=0.03
1.0
P=0.17
2.11
0.08
0.0
-0.1 -0.06
%Stenosis
-1.0
-2.0
MinDiam
-0.06
MeanDiam
Placebo
Fenofibrate
Fenofibrate Adverse Events
 Generally well tolerated
 Most frequent discontinuation - rash (6% vs 2%)
 Other events: pruritis, constipation, diarrhea
 G.I. Upset 2% ( less than placebo)
 LFTs elevations 6.3% vs 2.1% for placebo
 Increased warfarin levels (monitor INR)
PPARs are the
CENTER of the UNIVERSE
Peroxisome Proliferator Activated Receptor
PPARα -- Fibrates
PPARγ -- 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
30
23
20
• 9 patients
10
• 6 weeks
0
1 g/d N-3 PUFA
1 U tocopherol/d
-10
• 6 weeks
5 g/d fish oil
-20
TG
VLDL TG
VLDL-C
LDL
-30
• Slower VLDL and
LDL oxidation
-40
-40
-50
-60
-54
-56
Hau et al. Arterio Thromb Vasc Biol 1996;16:1197
Fish Oil vs Gemfibrozil
40
30
33.6
29.7
17.1
20
11.0
10
0
-10
LDL
HDL
TG
-20
-30
-40
-37.1
-40.4
-50
FO
Gemfib
Gemfibrozil 1,200 mg/d
Fish 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
•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
De Lorgeril et al Circulation 1999;99:779
Lyon Heart Trial
Survival with:
No MI
Survival with:
No MI
Angina
CHF
CVA
PE
Periph embol
Survival with:
No MI
Angina
CHF
CVA
PE
Periph embol
Stable angina
PTCA, CABG
Restenosis
De Lorgeril et al Circulation 1999;99:779
Lyon Heart Trial
Differences in LDL-C
LDL
Control
(n=204)
4.23 mmol/L
163.6 mg/dL
Intervention
(n=219)
4.17 mmol/L
161.3 mg/dL
De Lorgeril et al Circulation 1999;99:779
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
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 AND
ADMINISTRATION).
Crestor Package Insert
Special Considerations
Central Obesity Contributes to Insulin Resistance
Abdominal fat:
high rate of FA turnover
high rate of lipolysis
Diabetes and Lipids
• Elevated LDL
• Elevated TG’s
• Low HDL
LDL Sizing
• Ultracentrifugation
• NMR
• Gel elecrophoresis
A
B
Diabetes Atherosclerosis Intervention Study
DAIS
1. DM II,
2.
3.
4.
5.
with and without coronary intervention
Randomized, prospective
fenofibrate vs placebo
418 randomized
Follow-up - 39.6 months
End-points
minimum lumen diameter
mean segment diameter
mean % stenosis
Diabetes Atherosclerosis Intervention Study
DAIS
Change in Percentage Diameter Stenosis
Variable
LDL size + LDL
LDL size + apoB
LDL size + HDL
LDL size + TG
LDL size + LDL +
apoB + HDL + TG
* = P < 0.001
All
(n=405)
0.039*
0.041*
Fenofibrate
(n=198)
0.073*
0.078*
Placebo
(n=207)
0.008
0.008
0.026**
0.027**
0.044**
0.041**
0.056**
0.082**
0.016
0.007
0.021
** = P < 0.05
Effect of Exercise on Lipids
2906 men
age 30-64 years
exercise treadmill test to exhaustion
classified into 6 groups based on
average miles run per week
Kokkinos Arch Int Med 1995:155:415
Effect of Exercise on Lipids
LDL, TG, HDL versus miles per week
60
140
120
HDL mg%
100
80
50
60
40
45
LDL mg%Y2
55
HDL
LDL
TG
20
40
0
0-2 mi
3-6 mi
7-10 mi
11-14 mi
15-20 mi
21-60 mi
Miles Run per Week
Kokkinos Arch Int Med 1995:155:415
Trans-Fatty Acids
Lichtenstein NEJM 1999;340:1933
Trans-Fatty Acids
Lichtenstein NEJM 1999;340:1933
Summary
• Elevated TG’s are a risk factor
atherosclerosis
pancreatitis
• Treat underlying cause
• Use fibrates early
• Use in combination carefully
End
Hypertriglyceridemia
• Familial chylomicronemia
deficiency or inhibitor of LPL or activator Apo C-II
eruptive xanthomas, abdominal pain
diet Rx -- short-chain fatty acids
• Dysbetaliproproteinemia
homozygous for Apo E-2
high IDL -- chylo and VLDL remnants accumulate
diet therapy
• Familial endogenous hypertriglyceridemia
• Familial combined hyperlipidemia
Diet
Digestion