Approach to the Management of Hypertriglyceridemia

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Approach to theManagement ofHypertriglyceridemia
Timothy A. Denton, M.D. Attending
Cardiologist High Desert Heart Institute Victorvil
le, CA
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Outline

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

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Can you identify these?
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Chylomicrons
VLDL
E
B100
E
B100
AI
HDL1
AII
AI
AIV
AII
CI
CIII
CII
CII
B48
HDL2
B100
IDL
CI
AI
CII
CIII
AII
E
Remnants
E
HDL3
B100
LDL
AI
B48
AII
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Chylomicrons
800-5000 A
VLDL
HDL1
300-800 A
120-180 A
IDL
HDL2
250-350 A
90-120 A
LDL
180-280 A
HDL3
Remnants
50-90 A
gt300 A
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Egg McMuffin
Calories 290 Calories from fat 110 Total fat 12
g Saturated fat 4.5 g Cholesterol 235
mg Sodium 790 mg Carbohydrates 27g Protein 17g
http//www.mcdonalds.com/countries/usa/
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Chylomycron Production
Intestinal Brush Border
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Triglyceride Concentration over Time
Ng et al. Arterio Thromb Vasc Biol
1995152157-2164
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Lipids
C 8 - 24
Fatty Acids
HO
O
O
O
Triglycerides
O
O
O
O
O
G
O
P
O
Phospholipids
O
O
O
O
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Fatty Acid
Cholesterol
O
OH
C
HO
Cholesterol Ester
O
O
C
H O H
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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

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Fatty Acids
H
H
H
H
cis
C
C
C
C
C
C
H
H
H
H
H
H
H
H
H
H
H
trans
C
C
C
C
C
C
H
H
H
H
H
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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 5 4 3 2 1
Common name - ?-Linoleic
acid Systematic name - all
cis-9,12-octadecadienoic acid Systematic name
- cis-9, cis-12-octadecadienoic
acid Chemists name - 182 (9Z, 12Z)
(Zcis, Etrans) Chemists name -
182 ?9,12 (assume cis, indicate
trans) Nutritionists name 1 - 182
(n-6) Nutritionists name 2 - 182 ?-6
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REALLY, REALLY Essential Fatty Acids
Corn oil Cotton seed oil Linseed oil
(flax) Rapeseed (canola) oil Soya oil Walnut oil,
walnuts Peanuts Beef Spinach Fish
oils eicosa docosa Sardines, Salmon, Mackerel,
Cod, Halibut, Herring, Trout, Tuna, Haddock
Linoleic acid (182, n-6)
O
HO
?-Linolenic acid (183, n-3)
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Lipid Metabolism
Chylomicron
VLDL
Gut
What you eat
IDL
LIPOPROTEIN LIPASE
What you make
Fatty acids
Chylomicron remnant
Bile
LDL
300 mg/day
1,000 mg/day
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Lipemia
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Chylomicron Metabolism
Apo A-1
Apo B-48
cholesterol
Apo A-IV
phospholipid
cholesterol ester
triglyceride
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
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Fatty Acid Transport
Triglyceride-rich lipoprotein
Triglyceride synthesis
Liver
Apo C-II
Fatty acids

Adipose tissue
lipase
Fatty acids
FATTY ACID-ALBUMIN COMPLEXES
Triglyceride storage
Lipoprotein lipase
Energy
Muscle
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LDL and IDL
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Metabolism of VLDL
Apo B-100
HDL
Nascent VLDL
Cholesterol esters
Apo C-II, C-III
Apo E
Mature VLDL
Apo E

Apo C-II
Fibrates
Liver
LIPOPROTEIN LIPASE

Apo E
Apo C-III
Apo C-II,C-III
LDL
Phospholipids
VLDL Remnant
Fatty acids
HDL
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Etiology

• Genetic Familial dysbetalipoproteinemia Familia
  l 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

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Fredrickson Classification
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LDL Cholesterol Goals and Cutpoints for
Therapeutic Lifestyle Changes (TLC)and Drug
Therapy in Different Risk Categories
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Approach to the treatment of Hypertriglyceridemia

• Elevated TGs gt200 mg/dl
• Abdominal TGs gt500-1000 mg/dl

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Therapy of Hypertriglyceridemia

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

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Underlying Cause

• EtOH
• DM
• Obesity
• HIV drugs

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Underlying Cause
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Central Obesity Contributes to Insulin Resistance
Abdominal fat high rate of FA turnover high rate
of lipolysis
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Classic Diabetic Lipid Pattern

• Low HDL
• High LDL
• High TGs

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HIV Drugs

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

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Diet
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Lifestyle Heart Trial
Ornish D, et al. Lancet 1990336129
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Lifestyle Heart Trial
Ornish D, et al. Lancet 1990336129
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Dietary Goals

• NOT total fat reduction
• Total fat 10-20

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Partial Ileal Bypass
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POSCH -- Program On Surgical Control of
Hyperlipidemias
Arch Int Med 19981581253
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Drugs

• Statins
• Niacin
• Fibrates
• Fish oil

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Statins
Prava Simva Atorv Rosuva
Jones et al. Am J Cardiol200392152
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Niacin
Nicotinic acid Niacin (Vit B3)
Nicotinamide (no antilipemic activity)
O
O
HO
NH2
N
N
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Niacin Forms
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Niacin Onset of Action
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Apo B Pathway
Apo B-100
HDL
Nascent VLDL
Cholesterol esters
Apo C-II, C-III
Apo E
Mature VLDL
Apo E

Apo C-II
Niacin
Niacin
Liver
LIPOPROTEIN LIPASE

Apo E
Apo C-III
Apo C-II,C-III
LDL
Phospholipids
VLDL Remnant
Fatty acids
HDL
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Fibrates
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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 1999341410
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Effect of Fibrates on Lipid Levels
VA-HIT NEJM 1999341410
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Effect of FenoFibrate on Lipid Levels
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LDL Profile of Fenofibrate
Change
Caslake Arterioscler Thromb 199313702-11
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BIP
Bezafibrate Infarction Prevention Study
Circulation 200010221-27
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Diabetes Atherosclerosis Intervention StudyDAIS

1. DM II, with and without coronary intervention
2. Randomized, prospective fenofibrate vs placebo
3. 418 randomized
4. Follow-up - 39.6 months
5. End-points minimum lumen diameter mean segment
   diameter mean stenosis

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Diabetes Atherosclerosis Intervention StudyDAIS
P0.02
P0.03
P0.17
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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)
  

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PPARs are theCENTER of the UNIVERSE
Peroxisome Proliferator Activated Receptor PPARa
-- FibratesPPAR? -- Thiazolidinediones
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• PPARa Stimulation
• Reduces production of Apo CIII (inhibitor of
  lipolysis)
• Activates Lipoprotein Lipase
• Fall in TG levels
• Switch from small dense to large fluffy LDL
• Increases synthesis of Apo AI and AII

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Fish Oil

• n-3 PUFAs
• Epidemiologic data on survival
• GISSI-Prevenzione
• Effects on Triglycerides

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Fish Oil

• 9 patients
• 6 weeks 1 g/d N-3 PUFA 1 U tocopherol/d
• 6 weeks 5 g/d fish oil
• Slower VLDL and LDL oxidation

Hau et al. Arterio Thromb Vasc Biol 1996161197
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Fish Oil vs Gemfibrozil
Gemfibrozil 1,200 mg/d Fish oil 4g/day
Stalenhoef et al Atherosclerosis 2000153129
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n-3 PUFAs and SCD
Albert et al NEJM 20023461113
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GISSI-Prevenzione
GISSI group, Lancet 1999354447
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Mediterranian Diet
J. THOMSON "Chart of the Mediterranean Sea"
Edin.18I7
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Lyon Heart Trial

• lt35 energy as fat
• lt10 energy saturated fat
• lt4 energy as linoleic acid
• gt0.6 of energy as alpha-linolenic
  (183 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

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

De Lorgeril et al Circulation 199999779
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Lyon Heart Trial
Survival with No MI
Survival with No MI Angina CHF CVA PE Periph
embol Stable angina PTCA, CABG Restenosis
Survival with No MI Angina CHF CVA PE Periph
embol
De Lorgeril et al Circulation 199999779
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Lyon Heart Trial
Differences in LDL-C
De Lorgeril et al Circulation 199999779
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Plasmapheresis

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

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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 LFTs
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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
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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
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Special Considerations
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Central Obesity Contributes to Insulin Resistance
Abdominal fat high rate of FA turnover high rate
of lipolysis
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Diabetes and Lipids

• Elevated LDL
• Elevated TGs
• Low HDL

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LDL Sizing

• Ultracentrifugation
• NMR
• Gel elecrophoresis

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Diabetes Atherosclerosis Intervention StudyDAIS

1. DM II, with and without coronary intervention
2. Randomized, prospective fenofibrate vs placebo
3. 418 randomized
4. Follow-up - 39.6 months
5. End-points minimum lumen diameter mean segment
   diameter mean stenosis

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Diabetes Atherosclerosis Intervention StudyDAIS
Change in Percentage Diameter Stenosis
P lt 0.001 P lt 0.05
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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 1995155415
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Effect of Exercise on Lipids
Kokkinos Arch Int Med 1995155415
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Trans-Fatty Acids
Lichtenstein NEJM 19993401933
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Trans-Fatty Acids
Lichtenstein NEJM 19993401933
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Summary

• Elevated TGs are a risk factor atherosclerosis
  pancreatitis
• Treat underlying cause
• Use fibrates early
• Use in combination carefully

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End
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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

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Diet
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Digestion