Role of Triglyceride-enriched Lipoproteins in...

Highlights from Lipid Forum 2015: Focus on Hypertriglyceridemia

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Role of Triglyceride-enriched

Lipoproteins in Atherogenesis

Peter P. Toth, MD, PhD, FAAFP, FICA, FNLA,

FCCP, FAHA, FACC Director of Preventative Cardiology

CGH Medical Center, Sterling, Illinois

Professor of Clinical Family and Community Medicine

University of Illinois School of Medicine, Peoria, Illinois

Professor of Clinical Medicine

Michigan State University College of Osteopathic Medicine

East Lansing, Michigan

Adjunct Associate Professor

Johns Hopkins University School of Medicine, Baltimore, Maryland

Triglycerides and Remnant

Lipoproteins

• Severe hypertriglyceridemia is an established risk factor for pancreatitis.

• Elevated triglycerides also correlate with increased risk for acute cardiovascular events.

• Triglycerides are hydrophobic and do not circulate freely. They are carried in plasma by lipoproteins.

• Hypertriglyceridemia is associated with elevated remnant lipoproteins.

• A remnant lipoprotein is a lipoprotein whose triglyceride content is incompletely hydrolyzed, thereby preventing its progressive conversion to smaller lipoproteins (ie, VLDL to IDL to LDL).

• Though definitions may vary, in the nonfasting state, remnants include chylomicron remnants, VLDL remnants, and IDL; in the fasting state VLDL remnants (principally small VLDL3 and IDL).

• Remnants could be atherogenic because of both cholesterol and triglyceride components are carried into subendothelial space. Triglycerides are a source of diacylglycerol and free fatty acid, both of which can participate in augmenting the inflammatory response.



Remnant Lipoprotein Cholesterol

• Lipoprotein cholesterol as a function of increasing

levels of nonfasting triglycerides

– Increased levels of plasma triglycerides were

associated with increased levels of remnant cholesterol

and with reduced levels of HDL cholesterol, while

association with LDL cholesterol was less pronounced

Varbo A, et al. J Am Coll Cardiol. 2013;61:427–436.

Remnant Lipoproteins (RLPs)

• Serum lipids are measured typically after 8-12 hours of fasting.

• In Western societies, during routine daily living, the majority of people are

persistently post-prandial. In fact, meals tend to be consumed before the

lipids and lipoproteins from the preceding meal are fully metabolized and

cleared from the circulation.

• Consequently, we are exposed to much higher levels of RLPs and in a

more persistent manner than what is suggested by the results of studies

using fasting lipid samples.

• This would be especially true of patients afflicted with genetic variants of

hypertriglyceridemia (familial combined hyperlipidemia, familial

hypertriglyceridemia, a variety of lipoprotein lipase deficiency states),

insulin resistance, or established diabetes mellitus. As found in adults,

RLPs are elevated in obese or diabetic children and adolescents.

VLDL

IDL

LDLs

ApoB Lipoproteins

Chylomicron

HDL3

HDL2

ApoA-I Lipoproteins

Triglyceride

Free cholesterol

Cholesteryl ester

De

ns

ity, g/m

L

Diameter, nm5

2a2b

3b3a

3c

1020406080

1.02

1.006

0.95

Chylomicron Remnants1.06

Lp(a)1.10

1.20Phospholipids

1000

http://www.bhlinc.com/clinicians/clinical-references/reference-manual/chapter4



VLDL

IDL

LDLs

ApoB Lipoproteins

Chylomicron

HDL3

HDL2

ApoA-I Lipoproteins

Triglyceride

Free cholesterol

Cholesteryl ester

De

ns

ity, g/m

L

Diameter, nm5

2a2b

3b3a

3c

1020406080

1.02

1.006

0.95

Chylomicron Remnants1.06

Lp(a)1.10

1.20Phospholipids

1000

• The half-life of VLDL is about 30-60 minutes; the half-life of IDL is even

shorter

• The LDL particles have a much longer half-life in circulation (~2-3 days)

compared to chylomicrons, VLDLs and IDLs, and account for the bulk

of the plasma apoB-containing lipoproteins

• Directly measured apoB is considered roughly equivalent to the “LDL

particle number,” as generally 90%-95% of the apoB-containing

particles in circulation are actually LDLs

http://www.bhlinc.com/clinicians/clinical-references/reference-manual/chapter4

LPL

Apo C-III

ApoB

Apo C-II

ApoE

Angptl4

Angptl3

GPIHBP-1

Endothelial

cell

Angptl3 or 4 = angiopoietin-like proteins 3 and 4

GPIHBP1 = glycosylphosphatidylinositol anchored HDL binding protein

LPL = lipoprotein lipase

• Multiple proteins are at play in regulating lipolytic pathways

• ApoE, C-II, and apoA-V are activators of lipolysis

• C-III and Angptl 3 AND 4 are inhibitors

Lipolysis: Interaction of VLDL and LPL

Adapted from Chap 2 – Ballantyne CM. Clinical Lipidology. Philadelphia. Saunders; 2009.

Hypertriglyceridemia

• Severe hypertriglyceridemia (HTG) is

attributable to hyperchylomicronemia,

elevations in very low-density

lipoproteins and their remnants, or both1

• Hypertriglyceridemia is associated with

increased risk for cardiovascular events

and pancreatitis1

Genetic Polymorphisms that Cause

Severe HTG2

• Familial combined hyperlipidemia

• Hyperchylomicronemia

• Familial hypertriglyceridemia

• Dysbetalipoproteinemia

• Deficiency in lipoprotein lipase or

apoprotein CII

Secondary Etiologies for Severe HTG3,4

• Insulin resistance

• Diabetes mellitus

• Acromegaly

• Chronic kidney disease

• Iatrogenic effects from medications

(glucocorticoids, sirolimus)

It is important to further delineate how HTG is diagnosed and treated in the US and try to

further establish the relationship between HTG and

risk of pancreatitis

1. Toth PP, et al. Curr Atheroscler Rep. 2009;11:71-79; 2. Berglund L, et al. Best Prac Res Clin Endocrinol Metab. 2014;28:423-

437; 3. Kaysen GA. J Renal Nutr. 2009;19:73-77; 4. Stone NJ. Med Clin North Am. 1994;78:117-141.



Triglyceride (TG)–rich lipoproteins

(LPs) containing a single molecule

of apolipoprotein B are released

into the circulation by the liver or

intestine and bind the LPL on the

surface of endothelial cells

CETP activity and lipolysis of

TG-rich LPs by LPL yields a

TG-depleted but cholesterol-rich

remnant LP (RLP) which can

cross the endothelial barrier

Unlike native LDL, RLPs do not

have to be oxidatively modified and

can be taken up in an unregulated

fashion by scavenger receptors

expressed by resident

macrophages in the subendothelial

space, facilitating foam cell

formation and atherosclerosis

Remnant Lipoprotein Cholesterol

Varbo A, et al. J Am Coll Cardiol. 2013;61:427-436.

Artery Wall

Endothelium

Lipolysis

LPL

ApoB

Cholesterol-rich

remnant lipoprotein

Uptake of cholesterol-rich remnants by

macrophages leading to foam cells

Postprandial Change in Lipids and Flow

Mediated Dilation after Oral Fat Load

Reprinted with permission from Maggi FM, et al. J Clin Endocrinol Metab. 2004;89:2946-2950.

0h 2h 4h 6h 8h

0h 2h 4h 6h 8h

0h 2h 4h 6h 8h2

3

4

5

6

7

10

12

14

16

18

0.4

0.7

0.8

0.9

1.0

0.6

0.5

mm

ol/L

% D

ilati

on

mm

ol/L

FMD

Remnant-C

Triglycerides 15 moderately overweight &

dyslipidemic men with

baseline TG of 210 and

HDL-C of 39 given an oral

fat load

TG & RLP-C increased

significantly and

continuously up to 4 & 6

hours respectively

FMD revealed decreased

vasodilation at 4-6 hours

RLP contribute significantly

to impair endothelial dilation

Oral Triglyceride Tolerance Test

Reprinted with permission from Mohanlal N, Holman RR. Diabetes Care. 2004;27:89-94.

Time After Oral Fat Load (hours)

Nondiabetics Diabetics

80

40Tri

gly

ce

rid

es

(m

g/d

L)

0 2 4 6 8

320

280

240

200

120

160

80

40

0 2 4 6 8

320

280

240

200

120

160



Postprandial Triglyceride Levelsin Subjects With and Without Coronary Artery Disease

• Time elapsed between ingestion of the test meal and the triglyceride peak also distinguished cases from controls.

– A majority of cases (57.4%) displayed peak triglyceride concentrations at 6 hours after the test meal and the majority of control subjects (67.5%) at 4 hours.

– Shape of average postprandial triglyceride curves differed conspicuously in that curve was still rising between 4 and 6 hours in cases while in control subjects it was already falling.

Patsch JR, et al. Arterioscler Thromb. 1992;12:1336-1345.

Women’s Health Study

Fasting versus Nonfasting Triglycerides

Reprinted with permission from

Bansal S, et al. JAMA. 2007;298:309-316.

Association of TG with Future CV Events Stratified by Time from Last MealTime from last

meal, hrs# patients # Events

Hazard ratio

(95% CI)

2 - < 4

4 - 8

8 - 12

≥ 12

2707

2504

4846

15272

08

02

177

600

4.48 (1.08-10.15)

1.50 (0.72-3.13)

1.31 (0.73-2.36)

1.04 (0.70-1.36)

Fully adjusted HR (95% CI)

101.00.5HR for highest (>147) vs lowest tertiles (≤ 90) of TG levels adjusted for age, BP,

smoking, hormone use, tertiles of total and HDL-C, DM, BMI & hs-CRP

0.5 1.0 10

Fully adjusted HR

0.5 1.0 10

Fully adjusted HR0.5 1.0 10

Fully adjusted HR

Myocardial Infarction

Ischemic Stroke

Revascularization

CV Death

All CV Events

Fasting NonfastingFasting

0.5 1.0 10

Fully adjusted HR

HDL-C ≥ 50 mg/dL

TG < 150 mg/dLTG ≥ 150 mg/dL

Association of TG with Individual CV

Endpoints according to fasting statusAssociation of High vs Low TG levels with future CV

events stratified by HDL-C level

HR using TG levels < 150 and HDL-C levels ≥ 50

mg/dL adjusted for age, BP, smoking, hormone use,

tertiles of total and HDL-C, DM, BMI & hs-CRP

TG < 150 mg/dL

HDL-C < 50 mg/dL

Nonfasting

TG ≥ 150 mg/dL

Women’s Ischemia Syndrome Evaluation

(WISE): The TG/HDL-C Ratio

Reprinted with permission from Bittner V, et al. Am Heart J. 2009;157:548-555.

Among women with suspected ischemia, the TG/HDL-C

ratio is a powerful independent predictor of all cause

mortality and cardiovascular events.

Kaplan-Meier curves for

freedom from

cardiovascular events

by TG/ HDL-C quartile.

Quartile 1 (Q1) through

Q4 correspond to the

quartiles of TG/HDL-C

Excess risk of

cardiovascular events

is limited to

individuals in Q4 of

the TG/HDL-C

distribution.

Mean follow-up time for

surviving women was 5.3

±2.5 years (median 6.0

years, interquartile range

3.7-7.0 years).

0 1 2 3 4 5 6

0.9

1

0.8

0.7

0.6

Follow-Up years

Q1

Q2

Q3

Q4

0.35 < 1.4

1.4 - < 2.2

2.2 - < 3.66

3.66 – 18.4

For cardiovascular events,

the multivariate hazard

ratio was 1.54

(95% CI 1.05-2.22, P=.03)

Q4



Remnant Lipoproteins

• Whether triglycerides constitute an independent risk factor for atherosclerotic

cardiovascular disease (ASCVD) is controversial. A number of investigations

suggest that they are, though much depends on covariate adjustment. (Castelli WP. Am J Cardiol 1992;70:3H-9H; Miller M, et al. J Am Coll Cardiol.

2008;51:724-730; Miller M, et al. Circulation 2011;123:2292-2333.)

• The suggestion that RLPs contribute to atherogenesis was first made by

Zilversmit in 1979. (Zilversmit DB. Circulation 1979;60:473-485.)

• Remnants correlate significantly with risk for CV events.

• In the Framingham Offspring Study, serum levels of RLPs correlate with risk

for CV events in women with established coronary artery disease (CAD). (McNamara JR, et al. Atherosclerosis. 2001;154:229-236.)

• Similarly in the Honolulu Heart Study, serum levels of RLPs were significantly

associated with risk for CV events among men of Asian descent. (Imke C, et al. Arterioscler Thromb Vasc Biol. 2005;25:1718-1722.)

• In the ACCORD trial, RLPs correlated with CV events among diabetic women

in a postprandial substudy. (Ginsberg H, et al. N Engl J Med. 2010;362:1563-1574. )

Remnant Lipoproteins

• Remnant levels correlate with risk for acute CV events in Japanese patients

with established coronary artery disease (CAD), carotid intima media

thickness, carotid plaque macrophage density, ischemic stroke, endothelial

dysfunction, and can be extracted from atherosclerotic plaque. (Kugiyama K, et al. Circulation 1999;99:2858-2860; Karpe F, et al. J Lipid Res. 2001;42:17-21;

Zambon A, et al. Atherosclerosis. 2013;230:106-109; Kim JY, et al. J Clin Neurol 2011;7:203-209;

Maggi FM, et al. J Clin Endocrinol Metab. 2004;89:2946-2950; Rapp JH, et al. Arterioscler Thromb.

1994;14:1767-1774.)

• Among patients with Fredrickson type III dyslipoproteinemia (familial

dysbetalipoproteinemia; due to defective apoE), serum remnants are

increased leading to the development of xanthomas and elevated risk for CV

events. (Vermeer BJ, et al. J Invest Dermatol. 1992;98:57S-60S.)

• Remnants up-regulate the expression of pro-inflammatory cytokines, TNFα,

IL-6, VCAM-1 and ICAM-1, and MCP-1, and are directly cytotoxic to

endothelium. (Takeya M, et al. Hum Pathol.1993;24:534-539; Domoto K, et al. Atherosclerosis. 2003;171:193–

200; Twickler TB, et al. J Clin Endocrinol. Metab. 2003;88:1228–1233; Doi H, et al. Circulation.

2000;102:670–676).

Remnant Cholesterol as a Causal Risk

Factor for Ischemic Heart Disease

• As remnants progressively increase from first to fifth

quintile, there is a rising gradient of risk for future CHD

– A nonfasting remnant cholesterol increase of 1 mmol/L

(39 mg/dL) is associated with a 2.8-fold causal risk for

ischemic heart disease, independent of reduced HDL

cholesterol.

• Elevated cholesterol content of triglyceride-rich lipoprotein

particles causes ischemic heart disease.

Varbo A, et al. J Am Coll Cardiol. 2013;61:427-436.



Association of Nonfasting Remnant Cholesterol

and LDL Cholesterol with C-reactive Protein (CRP)

• 48,250 participants from the Copenhagen general

population study

• Elevated nonfasting remnant cholesterol is causally

associated with low-grade inflammation and with ischemic

heart disease, whereas elevated LDL cholesterol is

associated causally with IHD without inflammation

• As LDL levels progressively there’s a very nonsignificant

relationship between LDL and CRP

– Relationship between remnants and CRP: Significant 37%

increase in CRP as remnant levels rise

Varbo A, et al. Circulation. 2013;128:1298-1309.

Conclusions

• Elevated serum levels of remnant lipoproteins correlate highly with

heightened levels of systemic inflammation and increased risk for acute

cardiovascular events.

• Remnants represent a delivery vehicle for transferring cholesterol and

triglyceride into the subendothelial space where both can potentiate

atherogenesis.

• Clearly based on studies in Copenhagen, nonfasting triglyceride levels

represent a very good surrogate for remnants in serum.

• A host of separation methods can be used to quantify remnants (analytical

ultracentrifugation, ion mobility, electrophoresis, NMR). It will be of interest to

establish how accurately these various technologies estimate and separate

the distinct species of remnant lipoproteins in the serum and correlate each of

these species with cardiovascular outcomes.

• In the meantime, until uniform and widely accepted quantitative approaches

are adopted, the following has simple clinical utility and adds no cost:

– For nonfasting specimens, consider the Copenhagen approach.

– For fasting specimens, consider targeting non-HDL-C.

Secondary Hypertriglyceridemia–

Medications, Dietary and Lifestyle

Indiscretions, and Diseases

Alan S. Brown, MD, FACC, FAHA, FNLADirector, Division of Cardiology

Advocate Lutheran General Hospital

Director, Midwest Heart Disease Prevention Center

Midwest Heart Specialists at Advocate Healthcare

Chicago, IL



Secondary Causes of HTG: Practical Hints

• Do not blame it on the genes too quickly.

• Consider every form of severe HTG as secondary and search for

the cause.

• Think of alcohol as contributing cause if HDL is up with TG.

• Always get a direct LDL (low LDL is expected in exclusive HTG)

non HDL cholesterol and/or apoB.

• If LDL is high, combined dyslipidemia is likely to be genetically

determined.

• Do not be too stern on a fasting requirement.

• Consider a lipid panel 2 hours after a test meal

(ie, McDonald’s EVM1, QPC).

• Consider transient discontinuation of TG-lowering meds if you do

not know the patient’s lipid baseline or if you are curious whether

a panel adjustment is due to recent lifestyle adjustments.

Most Forms of HTG Are of Secondary Origin

HIV=human immunodeficiency virus.

Bays HE. In: Kwiterovich PO Jr, ed. The Johns Hopkins Textbook of Dyslipidemia. Lippincott Williams & Wilkins;2010:245-257.

Cause Additional details

Excess calories Nutrients or alcohol

Carbohydrates High-fructose foods, dietary fiber

Insulin resistance Chronic obesity, visceral adiposity, ethnicity

Diabetes mellitus Even if well controlled

Hypothyroidism If not adequately controlled with thyroid replacement therapy

Nephrotic syndrome

Medications

Antiretroviral regimens

Some phenothiazines and atypical antipsychotics

Nonselective beta-blockers

Thiazide diuretics

Oral estrogen, tamoxifen, glucocorticoids

Retinoids and rexinoids

Recreational drugs Marijuana (ApoC-III)

Prevalence of Hypertriglyceridemia

NHANES 1999–2008

Adapted from the AHA Scientific Statement. Miller M, et al. Circulation. 2011;123:2292-2333.

31

16.2

1.1

33

17.6

1.1

15.6

7.6

0.4

34.9

19.5

1.4

0

5

10

15

20

25

30

35

40

TG ≥150 mg/dL TG ≥200 mg/dL TG ≥500 mg/dL

~70 million persons (~1/3 of adult US population) have TG (≥150 mg/dL)

Pre

vale

nce o

f T

G a

t o

r exceed

ing

pre

-sp

ecif

ied

cu

t-o

ffs (

%)

Overall

White

Black

Hispanic



Why is Hypertriglyceridemia Common?

Maintenance of normal TG levels is the exclusive

responsibility of 1 extracellular enzyme – lipoprotein

lipase (LpL) – whose function depends on:

- Genetic integrity

- Secretion from parenchymal cells

- Transfer from liver to capillary endothelium

- Anchoring to capillary endothelium

- Effectively interacting with lipoproteins

Why is Hypertriglyceridemia Common?

Maintenance of normal TG levels is the exclusive

responsibility of 1 extracellular enzyme – lipoprotein

lipase (LpL) – whose function depends on:

- Genetic integrity – subtle mutations are common

(first hit)

- Secretion from parenchymal cells – sensitive to insulin

action

- Transfer from parenchymal to capillary endothelium –

subject to multiple modifiers

- Anchoring to capillary endothelium – subject to

competition from other molecules

- Effectively interacting with lipoproteins – blocking

auto-antibodies

Increasing TG Levels Increase

Risk of Pancreatitis

0.0

0.5

1.0

1.5

2.0

2.5

Crude Incidence (Cases/1000 patient-years)

Triglycerides (mg/dL)

Murphy MJ, et al. JAMA Intern Med. 2013;173:162-164.

≤150 (n=31,740)

150-499(n=31,887)

≥500(n=3642)

Group 1

Group 2

Group 3



Meta-analysis of 29 Studies Shows TG Level

Is a Significant CVD Risk Factor

*Individuals in top vs bottom third of usual log-TG values, adjusted for at least age, sex, smoking status, lipid concentrations, and (in most studies) blood pressure.

Adapted from Sarwar N, et al. Circulation. 2007;115:450-458.

Groups CHD Cases

Duration of Follow-up

≥10 years 5902

<10 years 4256

Sex

Male 7728

Female 1994

Fasting Status

Fasting 7484

Nonfasting 2674

Adjusted for HDL-C

Yes 4469

No 5689

Overall CHD Risk Ratio*

Decreased

Risk

CHD Risk Ratio*

(95% CI)

1.72 (95% CI, 1.56-1.90)

21Increased

Risk

N=262,525

Top Tertile of TG

defined as

>181 mg/dL

Lowest Tertile of

TG defined as

<120 mg/dL

PROVE IT-

TIMI 22 Trialb

TG ≥150 mg/dL Predicts Higher CHDa Risk

in Statin Takers with LDL-C <70 mg/dL

CH

D E

ven

t R

ate

aft

er

30 D

ays

c(%

)

aDeath, MI, and recurrent ACS. bACS patients on atorvastatin 80 mg or pravastatin 40 mg. cAdjusted for age, gender, low

HDL-C, smoking, hypertension (HTN), obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and

treatment. CHD=coronary heart disease; HR=hazard ratio; PROVE IT-TIMI=Pravastatin or Atorvastatin Evaluation and

Infection Therapy Thrombolysis In Myocardial Infarction.

Miller M, et al. J Am Coll Cardiol. 2008;51:724-730.

(N=4162)

11.7%

16.5%

TG <150 mg/dL TG ≥150 mg/dL

LDL-C <70 mg/dL

HR: 0.72

P =.017

HR: 0.84

P =.192

Referent

LDL-C ≥70 mg/dL

TG ≥150 mg/dL

Event Rate = 17.9%

0

10

15

20

5

High TG and Low HDL-C Correlate with CVD Risk

Even When LDL-C is Well Controlled

5-y

r R

isk o

f M

ajo

r

CV

D E

vents

(%

)

Patients with LDL-C ≤70 mg/dL on statina,b

HDL-C and TG values in mg/dLaOn-treatment level (3-month statin therapy), n=2661bMean LDL-C 58 mg/dL, mean TG 126 mg/dL

*P=.03 for differences among quintiles of HDL-C

HR vs Q1* 0.85 0.57 0.55 0.61

TNT=Treating to New Targets

Reprinted with Permission from

Barter P, et al. N Engl J Med. 2007;357:1301-1310.

TNT Study

0

2

4

6

8

10

39% Lower Risk

TG=147

TG=186TG=166

TG=122TG=139

Q1 Q2 Q3 Q4 Q5

<37 37 to <42 42 to <47 47 to <55 ≥55

HDL-C

Quintilesa



Meta-analysis with >1 Million Subjects

Reaffirms Link between Plasma TG and Death

33 studies on CVD mortality (17,018 CVD deaths among 726,030 subjects) and

38 studies on all-cause mortality (58,419 all-cause deaths among 330,566 subjects)

Median duration of study follow-up was 12.0 years.

Studies in subjects with diabetes, CVD, dyslipidemia or cancer were excluded.

Liu J, et al. Lipids Health Dis. 2013;12:159.

CVD mortality All-cause mortality

TG quartile (mg/dL) RR P RR P

I. <90 0.83 .001 0.94 .15

II. 90 to <150 (referent) 1.00 1.00

III. 150 to <200 1.15 .015 1.09 .011

IV. >200 1.25 .013 1.20 .011

Genetic Causes of Hypertriglyceridemia (HTG)

Common

• Familial combined hyperlipidemia (FCHL)– Variable ↑TG and cholesterol genetic defects in lipoprotein metabolism

• Familial hypertriglyceridemia (FHTG)– ↑TG levels only, related to ↑hepatic VLDL production and/or polygenic vs

environmental ↓lipoprotein lipase (LPL) activity

Rare

• Familial dysbetalipoproteinemia (Fredrickson Type III)

• LPL deficiency

• ApoC-II deficiency

• GPIHBP1 deficiency

• ApoA-V mutations

• Lipase maturation factor 1 deficiency (LMF1)

Bays HE. In: Kwiterovich PO Jr, ed. The Johns Hopkins Textbook of Dyslipidemia. Lippincott Williams & Wilkins;2010:245-257.

Genetic testing for causes of HTG is not useful clinically and is not

recommended as a routine practice

Reduced ApoC-III Loss-of-function Mutations

Show Reduced CHD Risk

The TG and HDL Working Group of the Exome Sequencing Project, NHLBI.

Crosby J, et al. New Eng J Med. 2014;371:22-31.

Loss-of-function

mutations reduced

TG levels by 39%

Odds ratio of CHD of subjects with any of 4 APOC3 loss-of-function mutations

among 110,970 participants (34,002 patients with CHD and 76,968 controls) in

14 studiesStudy Ancestry CHD Odds Ratio

WHI EA 0.39

WHI AA 0.00

FHS EA 0.00

MDC-CVA EA 1.70

ARIC EA 0.59

ARIC AA 2.40

IPM EA 0.74

IPM HA 0.51

IPM AA 0.62

ATVB+VHS EA 0.43

OHS EA 0.35

PROCARDIS EA 0.56

HUNT EA 0.86

GoDARTS CAD EA 0.00

EPIC CAD EA 1.00

FIA3 EA 0.00

German CAD EA 0.54

WTCCC EA 0.98

All 0.60

0 1 2 3 4 5



Treating the Underlying Factors

• Dietary intervention (fats, sugars, alcohol, calories)

• Body weight management

• Physical activity to activate beta-oxidation

• Treat underlying co-morbidities

• Evaluate options for changing TG-raising medications

Treating Hypertriglyceridemia

• Omega-3 fatty acids, prescription

• Fish oil, krill oil, flax seed supplementation

• Fibrates

• Niacins

• Statins

• Novel drugs and pathways

Conclusions

• Consider every hypertriglyceridemia as secondary, even the most severe.

• Hypertriglyceridemia is common because LpL is an easy target of genetic and non-genetic modifiers.

• Investigate and go after the primary cause.

• Aggressive lifestyle intervention produces large benefits.

1. TG can only go down if one does not eat.

2. The body burns fat after 40 minutes of aerobic activity.

• Use appropriate therapy of prescription omega 3 at full dose as the first complement to diet and exercise. Use fibrates for more resistant forms, and statins as appropriate for CV risk management.



Hypertriglyceridemia and

Pancreatitis


FCCP, FAHA, FACC

Director of Preventative Cardiology









Pancreatitis

• Severe hypertriglyceridemia (HTG) is etiologic for approximately 10%

of cases of acute pancreatitis and 56% of gestational pancreatitis.1

• Hypertriglyceridemia correlates with both:

– Increased availability of pro-inflammatory fatty acids produced by

pancreatic lipase, and

– Increased serum chylomicrons which can slow blood flow through

intra-pancreatic capillaries.2

• Serum triglyceride threshold for precipitating pancreatitis is

inadequately defined.

• The severity of pancreatitis induced by HTG is greater than with

gallstone or alcoholic pancreatitis (higher mortality and long-term

complications). There is no correlation between magnitude of HTG

and severity of pancreatitis.3

1 Anderson F, et al. Pancreatology. 2009;9:252–257.

2 Ewald N, et al. Curr Opin Lipidol. 2009;20:497-504.

3 Lloret Linares C, et al. Pancreas. 2008;37:13–22.

Very High TGs Can Cause

Acute Pancreatitis

Impact of Pancreatitis

• ~100,000 patients hospitalized

for acute pancreatitis in the

United States annually1

• ~2000 patient deaths per year

from complications related to

acute pancreatitis1

• Elevated TG or

chylomicronemia is the

underlying cause in up to 7%

of all acute pancreatitis cases

• Critical to recognize and

appropriately manage these

patients at risk, as most can be

effectively treated with lifestyle

modification and drug therapy2

0

20

40

60

80

100

Perc

en

t o

f P

ati

en

ts

Gallstones Alcohol TotalIdiopathic

Causes of Acute Pancreatitis1

Other (incl. TGs, meds, etc.)

1. Stevens T, Conwell DL. Acute Pancreatitis. Available at http://www.clevelandclinicmeded.com/medicalpubs

/diseasemanagement/gastroenterology/acute-pancreatitis. Accessed December 30, 2013.

2. Gan SI, et al. World J Gastroenterol. 2006;12:7197-7202.



Chylomicrons Suspected of Causing

Acute Pancreatitis

• Large TG-rich chylomicrons (CMs) are present in the circulation when serum TG levels exceed 885 mg/dL

• Size of particles can impair circulatory flow in capillary beds

• TGs, but not cholesterol or glucose, associated with pancreatitis

• CMs and remnants can impair pancreatic capillary blood flow

• Can lead to ischemia, disrupting the acinar structure & exposing CMs to pancreatic lipase

• Produce pro-inflammatory, non-esterified free fatty acids, damaging the acinar cells and microvasculature

• Resulting inflammatory cascade of cytokines & free radicals may lead to necrosis, edema, and inflammation of the pancreas

Pancreatitis

Mechanisms Through Which Hypertriglyceridemia

Causes Pancreatitis Are Not Fully Elucidated

Chylomicrons

and the Pancreas

Chylomicrons Are

a Prime Suspect

Gan SI, et al. World J Gastroenterol. 2006;12:7197-7202.

Severe Acute Pancreatitis Caused by Very High TGs

May Result in Increased Morbidity and Mortality

1. Scherer J, et al. J Clin Gastroenterol. 2013;48:195-203.

2. Steffanutti C, et al. Ther Apher Dial. 2013;17:130-137.

3. Deng et al. World J Gastroenterol. 2008;14(28):4558-4561.

0%

10%

20%

30%

40%

TG<500 mg/dL

TG≥500 mg/dL

• >90% have abdominal pain; nausea & vomiting in 80%

– Sharp pain in UL quadrant/ epigastric region radiating

to back, hips, lower abdomen & chest

• Mild cases: Restlessness,

fever, epigastric tenderness

• Severe cases: Guarding,

reduced bowel sounds, signs of HTN, possible shock, etc.

• Diagnosis: Supported by elevation of serum amylase & lipase levels (>3x normal)

Clinical Presentation2 Mortality Among Adults with

Severe Acute Pancreatitis3

Genetic Factors:

• Familial combined hyperlipidemia

• Familial hypertriglyceridemia

• Familial dysbetalipoproteinemia

• Familial chylomicronemia

Secondary Factors:

• Untreated and/or poorly controlled diabetes

• Alcohol abuse

• Pregnancy

• Medications

Causes of HTG Associated

with Pancreatitis1

Incidence of Pancreatitis by TG Level

Effect of TG Level on Acute Pancreatitis Risk

• Significant dose response

relationship between TG

level and incident AP

(adjusted HR, 1.04

[95% CI, 1.02-1.05])

• Risk of incident acute

pancreatitis increased by

4% for every 100 mg/dL

increase in TG level*

Incidence of Acute Pancreatitis

0.0

0.5

1.0

1.5

2.0

2.5

Crude Incidence (cases per 1000 patient–years)

Triglycerides

≤149 mg/dL

(n=31,740)150-499 mg/dL

(n=31,887)≥500 mg/dL

(n=3642)

Group 1

Group 2

Group 3

*After adjustment for covariates and removal of patients hospitalized for gallstones,

chronic pancreatitis, alcohol-related morbidities, renal failure, and other biliary disease

Murphy M, et al. JAMA Intern Med. 2013;173:162-164.



Pancreatitis

1Wang GJ, et al. World J Gastroenterol. 2009;15:1427-1430. 2Felderbauer P, et al. Basic Clin Pharmacol Toxicol. 2005;97:342-350. 3Makhija R,et al. J Hepatobiliary Pancreat Surg. 2002;9:401-410.

• Acute pancreatitis develops when intracellular mechanisms to inhibit

trypsin activation are overwhelmed by biochemical/structural injury.1

NF-kB activation Increases production of

Acute pancreatitis-1 TNF-alpha Interleukins

MCP-1Adhesion molecules

Selectins

Drive and sustain the inflammatory mediator “storm”

Pancreatitis induction depends on a cascade of events2,3

intracellular

Ca(II)

intracellular

pH

Cathepsin B activation

Acinar cell cytoskeleton

disruption

Mechanistic Basis for Pancreatitis

Frossard JL, Pastor CM. Front Biosci. 2002;7:d275-287.

VESSEL

Endothelium

Nerve

Ending

Pancreatic

Insult

PANCREAS

Neutrophil

1. Rolling

3. Migration 4. Infiltration and

enzyme release

Capillary Leakage

2. Adhesion

Selectins

Substance P

Superoxide

radicals

Cathepsin B

IL-5 IL-2

NK1R

Macrophage

Lymphocyte

Acinar cells

ICAM-1

CCR1

IL-6

TNF-α

MT-I

IL-1

Dismutase

Trypsin cascade

Acute phase

response

TNF-α

IL-10

Demographic Features of Pancreatitis

1. Among patients with fasting triglycerides >1500 mg/dL who develop acute

pancreatitis (AP), mean age was 46.4 years, and patients were predominantly

male.

2. Patients with AP likelier to have diabetes (52.7% vs 36.3%) and hypertension

(61.1% vs 47.2%) relative to patients without the condition, and to have liver

disease (16% vs 3.3%), alcohol abuse (21.4% vs 7.5%) and acute and chronic

pancreatitis (29.8% vs 2.3%) at baseline (all P<.001). Patients with acute

pancreatitis were found to have higher mean TG (3622 vs 2402 mg/dL) and total

cholesterol (492 vs 383 mg/dL) levels.

3. In a multivariable logistic regression model among patients with TG levels >1500

mg/dL, a 100 mg/dL increase in TG level was associated with a significant 4%

increase in the risk of an acute pancreatitis event over the follow-up period

(OR 1.04; 95% CI 1.03-1.05; P<.0001).

4. Higher TG ranges were typically associated with a higher risk of acute

pancreatitis, with a pronounced risk increase for TG levels >2000 mg/dL

(OR 12.8; 95% CI 8.8-18.6; P<.0001).

Toth PP, et al. Atherosclerosis. 2014;237:790-797.



Serum Triglyceride Levels and Risk

of Acute Pancreatitis

• As serum triglycerides rise there is a progressive

gradient rise in risk for acute pancreatitis

Toth PP, et al. Atherosclerosis. 2014;237:790-797.

Conclusions

1. Hypertriglyceridemia is an important risk factor for acute

pancreatitis.

2. Risk for pancreatitis becomes significant when serum

triglyceride levels exceed 1000 mg/dL. Above this value,

there is a rising gradient of risk for AP.

3. Triglyceride-bearing lipoproteins can induce alterations in

intra-pancreatic blood flow and trigger a massive

inflammatory response leading to the destruction of

acinar and beta-islet cell mass.

4. Complications of AP include diabetes mellitus,

pseudocyst, hemorrhage, chronic pain, chronic

pancreatitis, and death. 47

Pharmacologic Treatment of

Severe Hypertriglyceridemia


FCCP, FAHA, FACC

Director of Preventative Cardiology











Apo A-V: apolipoprotein A-V; CMR: chylomicron remnant; FFA: free fatty acid; HTGL: hepatic triglyceride lipase;

IDL: intermediate-density lipoprotein; LDL-R: LDL receptor; LPL: lipoprotein lipase; LRP:LDL receptor–related protein; VLDL:

very low-density lipoprotein; VLDL-R: VLDL receptor.

Overview of Triglyceride Metabolism

Reprinted with permission from Miller M, et al. Circulation. 2011;123:2292-2333.

CETP: cholesteryl ester transfer protein.

Metabolic Consequences of

Elevated Triglycerides

Reprinted with permission from Miller M, et al. Circulation. 2011;123:2292-2333.

Fibrates 30%-50%

Niacin 20%-50%

Omega-3 10%-40%

Statins 10%-30%

Ezetimibe 5%-10%

Effect of Lipid-lowering Therapies

on TG Reduction

Ballantyne CM, ed. Clinical Lipidology: A Companion to Braunwald’s Heart Disease. Philadelphia: Saunders/Elsevier;

2009;253-338.



Treating Hypertriglyceridemia:

Niacin Therapy

ER: extended release

Goldberg A, et al. Am J Cardiol. 2000;85:1100-1105.

Nicotinic Acid ER: A Broad

Spectrum Lipid-modulating Agent

• Dose-dependent effects on HDL-C, LDL-C, Lp(a),

and TG

On Statin, mg/dL

(n = 3,196)

Off Statin, mg/dL

(n = 218)

LDL-C (mean) 71 119

HDL-C (mean) 35 33

Triglycerides

(median)161 215

Non-HDL (mean) 107 165

ApoB 81 111

AIM HIGH: Baseline Lipids

AIM-HIGH Investigators. N Engl J Med. 2011;365:2255-2267.



AIM HIGH: Primary Outcome

Reprinted with permission from AIM-HIGH Investigators. N Engl J Med. 2011;365:2255-2267.

0.4 0.5 0.7 1.0 1.5Log HR and 95% CI

No 242 (16.2)

Yes 40 (16.7)

TG ≥ 200 and HDL < 32

No 234 (16.3)

Yes 48 (17.0)

224 (15.0)

50 (25.0)

220 (15.1)

54 (22.4)

TG ≥ 198 and HDL < 33a

No. Patients With Events

(% of Category)ERN

Better Worse

1.11 (0.93-1.33)

0.63 (0.40-0.98)

1.09 (0.91-1.31)

0.74 (0.50-1.09)

HR

(95% CI)

.017

.073

P b

Int.

a Highest tertile of TG and lowest tertile of HDL-C. b Heterogeneity by treatment.

ERN: extended-release niacin

Effect of High-risk Groups on

Primary Outcome

Adapted from Guyton JR, et al. J Am Coll Cardiol. 2013;62(17):1580-4.


Fibrate Therapy



a P<.001 vs simvastatin

SAFARI: Combination Therapy in

Patients With Combined Hyperlipidemia

Grundy SM, et al. Am J Cardiol. 2005;95:462-468.

N = 618

Study (Fibrate)

Primary Endpoint

(All Patients)

Lipid Criteria,

mmol/L

Primary

Endpoint

(Lipid Subgroup)

ACCORD

(fenofibrate/

simvastatin)

−8% (P=.32)TG ≥ 2.3 +

HDL-C ≤ 0.88−31%

FIELD

(fenofibrate)−11% (P=.16)

TG ≥ 2.3 +

low HDL-Cb −27% (P=.005)

BIP

(bezafibrate)−7.3% (P=.24)

TG ≥ 2.3 +

HDL-C ≤ 0.9−39.5% (P=.02)

HHS

(gemfibrozil)−34% (P<.02)

TG > 2.3 +

LDL/HDL > 5.0−71% (P<.005)

a Comparator treatments: simvastatin in ACCORD Lipid and placebo in other studies. b < 1.03 in men and < 1.29 in women.

Reduction in CV Eventsa: Fibrate Studies

Meta-regression for TG Lowering with Fibrates and

Reduction in Risk of a Major CV Event

Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

Consistent with results from genetic studies; each 1 mmol/L (88.5 mg/dL)

reduction in TG is equivalent to ~17.7 mg/dL reduction in TRL-C

Triglyceride reduction (mmol/L)

0.2 0.4 0.6 0.8 1.0




Omega-3 Fatty Acid Therapy

Relative Risk of Sudden Cardiac Death and Blood

Omega-3 Levels: Physicians’Health Study

FA: fatty acid

Albert CM, et al. N Engl J Med. 2002;346:1113-1118.

GISSI-Prevenzione:

Time Course of Clinical Events

• >11,300 post-MI patients were given usual care

with or without 850 mg EPA+DHA for 3.5 years

• Total mortality reduced by 28% (P=.027)

• Sudden death reduced by 47% (P=.0136)

Marchioli R, et al. Circulation. 2002;105:1897-1903.



Structure of Omega-3 and

Omega-6 Fatty Acids

Din JN, et al. BMJ. 2004;328:30-35.

Omega-6 fatty acids Omega-3 fatty acids

Population Recommendation

Patients without

documented

CHD

Eat a variety of (preferably oily) fish at least twice a

week; include oils and foods rich in alpha-linolenic

acid (flaxseed, canola, and soybean oils; flaxseeds;

and walnuts)

Patients with

documented

CHD

Consume ~1 g of EPA+DHA per day, preferably from

oily fish; EPA+DHA supplements could be considered

in consultation with the physician

Patients needing

triglyceride

lowering

2-4 g of EPA+DHA per day provided as capsules

under a physician’s care

AHA Recommendations for

Omega-3 Fatty Acid Intake

Kri-Etherton PM, et al. Circulation. 2002;106:2747-2757.

GISSI-Prevenzione: Effects of 850 mg/day

of EPA+DHA on Serum Lipids

• Compared with baseline values, total and LDL-C

levels increased slightly at 6 months and then

declined, reaching approximately the same levels

as measured at baseline.

• HDL-C levels were increased in a similar way in

active and control groups.

• Mean triglyceride values during follow-up were

155.1 mg/dL and 162.6 mg/dL for the n-3 PUFA

and control groups, respectively.

Marchioli R, et al. Circulation. 2002;105:1897-1903.



But … minimal (5%) net triglyceride-lowering effect

JELIS Study: Ethyl-EPA

Reduced CV Events

Yokoyama M, et al. Lancet. 2007;3369:1090-1098.

a Sudden cardiac death, fatal and non-fatal MI,

unstable angina, angioplasty, stenting, or CABG.

Addition of EPA to Statin Therapy in

Japanese Patients

TC: total cholesterol

Yokoyama M, et al. Lancet. 2007;369:1090-1098.

Patient Subgroup: TG > 150 mg/dL

and HDL < 40 mg/dL (JELIS)

Saito S, et al. Atherosclerosis. 2008;199:378-383.



Conclusions

1. The specific etiology for hypertriglyceridemia is variable, and includes genetic,

metabolic, and iatrogenic causes.

2. Statins reduce triglycerides in a dose-dependent manner, largely by decreasing

VLDL production and secretion.

3. The fibrates and omega-3 fish oils reduce VLDL production/secretion and

activate lipoprotein lipase.

4. Clinical trial experience with the fibrates is decidedly mixed, likely due to

shortcomings in design. In subgroup analyses, fibrate therapy reduces risk for

CVD in patients with the high triglyceride/low HDL-C phenotype.

5. The omega-3 fish oils reduced CV endpoints in GISSI-3 and JELIS. It remains to

be determined if triglyceride reduction with omega-3 agents in patients with

hypertriglyceridemia reduces risk for CVD events. STRENGTH and REDUCE-IT

trials are currently underway to evaluate this issue.

The Role of Diet and Exercise in

Managing Hypertriglyceridemia

R. Scott Wright, MDProfessor of Medicine

Mayo Clinic College of Medicine

Rochester, MN

Objectives

• Discuss evidence-based dietary and exercise recommendations for patients with hypertriglyceridemia

• Understand differences in recommendations for patients with mild, moderate, or severe hypertriglyceridemia or chylomicronemia



Dietary Management of


• Nutrition measurements that affect

triglyceride levels include:

– Body weight status

– Body fat distribution

– Weight loss

– Macronutrient profile of the diet

Type and amount of dietary carbohydrate and fat

– Alcohol consumption

Miller M, et al. Circulation. 2011;123:2292-2333.

Weight Loss

• Weight loss of 5% to 10% results in– 20% decrease in TG

– Approximate 15% reduction in LDL-C

– 8% to 10% increase in HDL-C

• Magnitude of decrease in TGs is directly related

to the amount of weight loss

• Meta-analyses: For every 1 kg of weight loss

TG decrease 1.9%, or 1.5 mg/dL


Macronutrient Composition in


• Dietary management of HTG goes beyond total fat intake– Dietary fat

Trans fat

Saturated fat

Monounsaturated fat

Omega-3 FA

– Carbohydrates


Reduction of macronutrient

intake = replacement with

alternative macronutrient



Carbohydrates and Lipogenesis

Patel G. Metabolism. faqs.org. http://www.faqs.org/nutrition/Met-Obe/Metabolism.html. Accessed March 20, 2015.

• Important interrelationships among CHO, fats, and proteins

• Carbohydrates - Generally go through glycolysis to produce ATP.

– This can be accomplished in the absence of oxygen but with a relatively low yield in energy or ATP. Pyruvate is also produced and, in the absence or deficiency of oxygen, is converted to lactic acid (lactate).

• Proteins - Deaminated in the liver and they can then enter the Krebs cycle at a couple of different spots and result in energy in this method:

– Because it must be deaminated (remove an ammonia group on a chemistry level) before this can occur, it takes more energy to break it down. ATP is produced as well as some intermediate products (NADH, FADH) that ultimately result in ATP after going through the Electron Transport System (ETS).

• Fats - Stored, and often consumed, in the form of triglycerides

– Fatty acids are removed and enter the mitochondria where they go through a process called 'Beta-Oxidation' where 2 carbon molecules are removed at a time. Fats can store a tremendous amount of energy within them. However, protein & fat catabolism requires oxygen in order to yield the energy needed.

Sugars and Triglycerides

Beil L. ScienceNews. https://www.sciencenews.org/article/sweet-confusion. Accessed March 20, 2015.

• Sucrose is a disaccharide consisting of 1

molecule of glucose and 1 molecule of fructose

Carbohydrates and

Hypertriglyceridemia: Fructose

Reprinted with permission from Fried SK, Rao SP. Am J Clin Nutr. 2003;78:873S-880S.

Because fructose bypasses a rate-limiting step in glycolysis, high

fructose influx promotes TG synthesis and VLDL production.

• Fructose is considered the most hypertriglyceridemic sugar

• Enhance lipogenesis and triglyceride synthesis



Fasting Plasma TG Concentrations

and Fructose Intake

Reprinted with permission from Livesey G, Taylor R.

Am J Clin Nutr. 2008;88(5):1419-1437.

An increase in

fructose intake is

associated with

an increase in

TGs in multiple

health states.

Dietary Carbohydrate Intake and TGs: Fiber

• Increases in TG and reduced HDL-C may occur

when carbohydrate is consumed with viscous

(soluble) fiber.

• It has not been demonstrated definitively that

viscous fiber can fully negate the TG-raising or

HDL-lowering actions of very high intakes of

CHOs.


Dietary Carbohydrate and TGs: Fiber

• Meta-analysis of 7 studies

compared moderate CHO and

high fiber vs moderate CHO and

low fiber in T2DM

– TG decreased by 8% in the

high-fiber groups

• Meta-analysis of 9 studies

(n=119) compared high CHO and

high fiber vs moderate CHO and

low fiber in T2DM

– TG decreased 13% in the

high-fiber group

• Data support TG-lowering effect

for dietary fiber (T2DM)


Anderson JW, et al. J Am Coll Nutr. 2004;23:5-17.





• 1) Implement a Mediterranean style diet

– Mean reduction in triglycerides 10%-15%

• 2) Add long chain omega-3 polyunsaturated fatty acids

– Mean reduction: 5%-10% per gram

• 3) Decrease carbohydrate intake (1% energy replacement

with monounsaturated or polyunsaturated fatty acids)

– Mean TG reduction: 1%-2%

• 4) Eliminate trans fats (1% replacement with

monounsaturated fatty acids or polyunsaturated fatty acids)

– Mean reduction: 1%-2%

HYPERTRIGLYCERIDEMIA: Diet Recommendations

High Triglycerides Very High Triglycerides

Carbohydrates 50%-55% 45%-50%

Added Sugars 5%-10% <5%

Fructose 50 g - 100 g <50 g

Protein 15%-20% 20%

Fat 30%-35%

trans fat AVOID

saturated fat <5%

monounsaturated fat 10%-20%

polyunsaturated fat 10%-20%

EPA/DHA 1-2 g >2 g

Alcohol Decrease consumption


Total Fat and HTG

• Meta-analysis of 19 studies published by IOM

– Relationship between % total fat intake and change in

TG and HDL-C concentrations

– Compared low-fat, high-CHO diets vs higher-fat diets

– For every 5% decrease in total fat, TG level was

increased by 6% and HDL-C to decrease by 2.2%


Reduction of macronutrient intake =

replacement with alternative macronutrient



Total Fat and HTG

• Meta-analysis of 30 controlled feeding studies in

patients with or without T2DM (n=1213)

• Moderate-fat diet (32.5% to 50% of calories from fat) vs

lower-fat diet (18% to 30% of calories from fat) resulted

in a decrease in TG level of 9.4 mg/dL (range 6.1 to 12.2

mg/dL, P<.00001) without T2DM

• In T2DM, moderate-fat diet resulted in greater TG

reduction (24.8 mg/dL, P=.05) than seen with the

low-fat diet







Protein 15%-20% 20%

Fat 30%-35%

trans fat AVOID

saturated fat <5%



EPA/DHA 1-2 g >2 g



Dietary Management of Hypertriglyceridemia

• Moderate intake of predominantly unsaturated fat

(≥30% to 35% of) and plant-based proteins (17%

to 25% of energy) may produce a TG-lowering

effect.




Types of Dietary Fat and HTG

• Meta-analysis of 60 controlled feeding studies

– Replacement of any fatty acid class with CHOs

increased fasting TG levels

– Each 1% isoenergetic replacement of CHOs,

decreases in TG resulted with

Saturated fat (SFA; 1.9 mg/dL)

MUFA (1.7 mg/dL)

PUFA (2.3 mg/dL)

All P =.001

– Approximate 1% to 2% decrease in TG levels


Trans Fats

• Eliminate dietary trans fatty acids

– TFA increase TGs and atherogenic lipoproteins (Lp[a], LDL-C)

• Small proportion of total caloric intake

– Bakery shortening and stick margarine contain high trans fatty

acid concentrations (30% to 50%)

• Each 1% replacement of trans fatty acids for

monounsaturated fat (MUFA) or polyunsaturated fat

(PUFA) lowers TGs by 1%







Protein 15%-20% 20%

Fat 30%-35%

trans fat AVOID

saturated fat <5%



EPA/DHA 1-2 g >2 g





Mediterranean Dietary Pattern and TGs

• Several RCTs have reported beneficial effects of

Mediterranean-style diet on TGs compared with

lower-fat diet.

• Mediterranean-style diet = more foods rich in

MUFA, PUFA, and dietary fiber.

• Total fruit, vegetables, nuts, whole grains, and

olive oil were higher in the intervention group.



• Intervention diet – 28% of calories from total fat, with 8%, 12%, and 8% of calories from SFA,

MUFA, and PUFA, respectively (reduced total fat, reduced SFA, increased MUFA and PUFA vs control)

• Control diet – 30% of calories from total fat, with 14%, 10%, and 7% of calories from SFA,

MUFA, and PUFA, respectively

• After 2 years, TGs decreased 19% in intervention group(P=.001 vs control diet)

• In addition, subjects on the intervention diet decreased body weight by 6.2 lb or 2.8 kg (P=.001) and waist circumference by 0.8 inches or 2 cm (P=.01) compared with the control group


Esposito K, et al. JAMA. 2004;292:1440-1446.


With few exceptions,

implementation of a

Mediterranean-style

diet vs low-fat diet is

more commonly

associated with an

approximately 10% to

15% lowering of TG

levels.


Vincent-Baudry S, et al. Am J Clin Nutr. 2005;82:964-971.

Salas-Salvado J, et al. Arch Intern Med. 2008;168:2449-2458.



Omega-3 Fatty Acids and HTG


• AHA recommends 2 to 4 g EPA and DHA

provided as capsules to lower TGs

• Large body of evidence showing TG-

lowering effects of marine-derived

omega-3 PUFA

• Dose-response relationship between

omega-3 PUFA and TG lowering

• Approximate 5% to 10% reduction in

TGs for every 1 g of EPA/DHA

consumed

• Efficacy is greater in individuals with higher

TG levels before treatment






Protein 15%-20% 20%

Fat 30%-35%

trans fat AVOID

saturated fat <5%



EPA/DHA 1-2 g >2 g



Alcohol and Hypertriglyceridemia

• Moderate alcohol intake has limited association with TG levels

• At higher intake, TGs increase:– 1 ounce per day = 5%-10% higher TG than in non-drinkers

• Nearly 1 in 5 hospitalized alcoholics have TG ≥ 250 mg/dL

• Exaggerated increase in TG with high SFA diet

• May be due to inhibition of LPL-mediated hydrolysis of chylomicrons









Protein 15%-20% 20%

Fat 30%-35%

trans fat AVOID

saturated fat <5%



EPA/DHA 1-2 g >2 g



97



• 1) Implement a Mediterranean style diet

– Mean reduction in triglycerides: 10%-15%

• 2) Add long chain omega-3 polyunsaturated fatty acids

– Mean reduction: 5%-10% per gram

• 3) Decrease carbohydrate intake (1% energy replacement

with monounsaturated or polyunsaturated fatty acids)


• 4) Eliminate trans fats (1% replacement with

monounsaturated fatty acids or polyunsaturated fatty acids)



Practical Algorithm for Screening and

Management of Elevated Triglycerides

• See Miller M, et al. Circulation. 2011;123:2292-2333.

http://circ.ahajournals.org/content/123/20/2292/F5.expansion.html



Physical Activity and HTG

• Sedentary lifestyle, visceral obesity, insulin resistance, high SFA intake– Increased content of intramyocellular TG

– Ineffective utilization of fat/reduced muscle fatty acid oxidation

• Aerobic activity enhances lipid oxidation– Facilitates hydrolysis and utilization of TG in

skeletal muscle


Physical Activity (PA) and HTG

• PA effect in lowering TG depends on:

– Baseline TG

– Caloric expenditure

– Duration of exercise

• PA most effective in lowering TG when baseline

levels >150 mg/dL, activity is moderate to

intensive, and total caloric intake is reduced

– Approximately 20%-30% decrease


Dietary Management of Acute Pancreatitis (AP)

and Severe HTG/Chylomicronemia

• Early aggressive IV hydration

– ≥250-500 mg/hr isotonic crystalloid solution

(Lactated Ringer’s preferred)

• Mild AP: oral feedings may be started immediately

– Low-residue, low-fat soft/solid diet as safe as clear liquid diet

– Bowel rest associated with intestinal mucosal atrophy and

infectious complications due to bacterial translocation from the gut

• Severe AP: enteral nutrition recommended

– Avoid parenteral nutrition

– Associated with infectious complications and line-related

complications

Tenner S, et al. Am J Gastroenterol. 2013;108:1400-1415.



Summary: Diet and HTG

• Weight loss and implementation of Mediterranean dietary pattern result in greatest reduction in TG

• Increase intake of marine-derived PUFA (EPA/DHA)

• Elimination trans fat and reduction of refined carbohydrates result in more modest reductions in TGs

• Eliminate or limit alcohol intake


Are All Omega-3 Fish Oils

the Same?

Examining the Evidence: EPA, DHA, or Both?

R. Scott Wright, MDProfessor of Medicine

Mayo Clinic College of Medicine

Rochester, MN

Overview of -3 Fatty Acids and

-3 Products

• Objectives

– Discuss differences in forms of EPA and DHA present

in available fish oil preparations.

– Understand differences in the amounts of -3 fatty

acids in currently available prescription fish oil products

and in OTC dietary supplements.

– Review differences in the effects of EPA and DHA

formulations on lipid, lipoprotein levels, and apoC-III.

DHA, docosahexaenoic acid

EPA, eicosapentaenoic acid



Overview of -3 Fatty Acids

and -3 Products

• Formulations

• Metabolism

• Bioavailability: Short-term, long-term

• Dosing: With or without high-fat meal

• EPA vs DHA

• Lipid / lipoprotein effects


• Long-chain omega-3 fatty acids are primarily found

in cold-water organisms.

• The High number of double bonds lowers the

melting point.

• At low temperatures, biological structures retain the

fluidity necessary for life processes.

• Coldwater fish, microalgae, and Antarctic krill are

the greatest sources.

Schuchardt J, Hahn A. Prostaglandins, Leukot Essent Fatty Acids. 2013;89:1-8.

Different Forms of EPA and DHA

• Triglyceride (triacylglycerol)

• Ethyl Ester

• Free Fatty Acid (carboxylic acid)

• Phospholipid





• Triglyceride (triacylglycerol)

– EPA or DHA, along with 2 other fatty acids, connected

to all 3 carbons of glycerol (3-carbon) backbone

– Predominant omega-3 form in food supply, including in

fish and seafood, fish oils, and re-esterified triglyceride



• Ethyl Ester

– EPA/DHA chemically connected to ethanol, allows the

ethyl ester forms of EPA/DHA to be concentrated via

molecular distillation to produce omega-3

“concentrates.”

– Used directly as sources of EPA/DHA in dietary

supplements, or can be converted back to the

triglyceride form for supplements (“re-esterified”

triglycerides).



• Free Fatty Acids (carboxylic acids)

– EPA/DHA fatty acids that are not connected to a

glycerol backbone, as they are in the triglyceride

and phospholipid forms, nor chemically linked to

ethanol as in the ethyl ester form





• Phospholipid

– EPA, DHA, and other fatty acids connected to a

glycerol (3-carbon) backbone so that 2 fatty acids are

present on 2 of the carbons, and 1 carbon is

associated with the “head group” of the phospholipid

– Minor components of most marine oils (krill oil)



• Metabolism

• Bioavailability

• Dosing

• Lipid/lipoprotein effects


Omega-3 Fatty Acids:

Ingestion to Tissue

• After emulsification of fats in the stomach, they enter small intestine where the n−3 FA are cleaved off from their various types of bonds to form free fatty acids and 2-monoacylglyceride (2-MAG). Free n−3 FA and 2-MAG are taken up as mixed micelles. Bile salts must also be present in small intestine to allow for incorporation of fatty acids and other fat digestion products into mixed micelles. Fat absorption from mixed micelles occurs throughout the small intestine and is 85%-95% efficient under normal conditions.

• In enterocytes, n−3 FA are re-esterified to triacylglycerides, which are then incorporated into chylomicrons and transferred via the basolateral membrane to the lymph and thus to systemic circulation. Blood then transports n−3 FA to the target tissues, where they are primarily incorporated in membranes.




Omega-3 Fatty Acids: Bioavailability


• Proposed differences in “bioavailability” based on formulation:

– Short-term availability based on levels in serum and plasma Omega-3 fatty acids not physiologically active in bloodstream

– Long-term availability in erythrocyte membranes Omega-3 index

Sum of EPA and DHA as percentage of total FA in erythrocyte membranes

Measure of long-term incorporation of FA in tissue

• Most studies of bioavailability evaluate only short-term availability

Davidson MH, et al. J Clin Lipidol. 2012;6:573-584.

ECLIPSE Study: Short-term

Bioavailability of FFA vs EE

• Randomized, open-label, single dose, 4-way crossover, bioavailability study of Omega-3 (OM-3) FFA and OM-3 EE administered during periods of low-fat and high-fat consumption to 54 overweight adults

• Baseline-adjusted AUC for total EPA + DHA during the low-fat period was 4.0-fold greater with OM-3 FFA compared with OM-3 EE

• During the high-fat period, AUC(0-t) for OM-3 FFA was approximately 1.3-fold greater than OM-3 EE

• Although a trend for greater bioavailability of total plasma EPA + DHA from krill oil was noted, likely attributable to the FFA content, plasma phospholipid AUC0-72 of EPA + DHA among all 3 treatments were not significantly different

Omega-3 Fatty Acids: Ingestion to

Tissue


Salem N, Jr., Kuratko CN. Lipids Health Dis. 2014;13:137.

• Short-term availability based on levels in serum and plasma

– Omega-3 fatty acids in TG and FFA forms appear to have better short-term availability compared to those in EE form

– EE form is more available when consumed with high-fat meal

– Limited information on bioavailability of omega-3 PL from krill oil compared to TG from fish oils, primarily animal studies

• Clinical or therapeutic implications of these differences are unknown

• Not valid to interpret differing absorption characteristics of a single dose as relevant to the efficacy of chronic therapy.




and -3 Products

• Currently 6 FDA-approved prescription fish oil

formulations are available for management of patients

with severe HTG (TG >500 mg/dL)

– 4 contain -3-acid ethyl esters (EPA and DHA)

2 branded, 2 generic

– 1 contains -3-carboxylic acids or free fatty acids (EPA

and DHA)

Branded

– 1 contains icosapent ethyl (EPA only)

Branded

Weintraub HS. Postgrad Med. 2014;126:7-18.

-3 FA Content of Available

Fish Oil Preparations

Product Active ingredient(s) EPA/DHA Content Dosing

ω-3-acid ethyl esters (Rx)

(n=4)

Ethyl esters of EPA/DHA Each 1 gram capsule

contains EPA ethyl ester

~465 mg and DHA ethyl

ester ~375 mg

2 grams twice daily or 4

grams once daily

Icosapent ethyl ester (Rx)

(n=1)

Ethyl ester of EPA only Each capsule contains 1

gram of icosapent ethyl ester

2 grams twice daily

Free fatty acids (carboxylic

acids) (Rx)

(n=1)

Free fatty acid forms of

EPA/DHA

Each 1 gram capsule

contains 75% EPA and DHA

in free fatty acid form

2 or 4 grams daily

OTC fish oil supplement EPA, DHA, primarily in

triglyceride form; other

components

Purity and amount of EPA

(median EPA 216 mg; range

160-360 mg) and DHA

(median 200 mg; range 120-

240 mg) varies per capsule

NR

OTC Krill oil supplements EPA and DHA as

phospholipids; other

components

Each 1 gram capsule

contains 30% EPA and DHA,

40% phospholipids, vitamin

A, vitamin E, other fatty

acids, astaxanthin

NR

Weintraub H. Atherosclerosis. 2013;230:381-389.

-3 FA: Ethyl Ester Preparations

• First -3 FA product approved in 2004 for

treatment of severe HTG (TG ≥ 500 mg/dL)

• Reduced baseline TG levels by up to 45%

in small, prospective, double-blind, RCTs

• LDL-C increased 17%-31%, likely associated

with the DHA and not the EPA component,

although both elicit TG-lowering effects

Jacobson TA, et al. J Clin Lipidol. 2012;6:5-18.

Omega-3-acid ethyl esters. Prescribing Information. Glaxo Smith Kline. 2008.



-3 FA: Icosapent Ethyl (EPA only)

• Icosapent ethyl approved for severe HTG (≥500 mg/dL)

in 2012

• -3 formulation without DHA

• Does not cause an increase in LDL-C

– 4-g daily dose reduced total LDL-C by 16.3%

– 2-g daily dose led to non-significant increase in LDL-C

• TG reduced 25%-45% with 4-g daily dose in multicenter,

placebo-controlled, randomized, double-blind, 12-week

study


-3 FA: Carboxylic Acid Form

• Approved for severe HTG in May 2014

• EPA and DHA in FFA form

– 50%-60% EPA and 15-25% DHA

• 12-week RCT (151 pts with severe HTG between

500 and 2000 mg/dL)

– TG reduced 33% compared to placebo

– No significant change in LDL-C or HDL-C

• Not yet commercially available


-3 FA: Dietary Supplement Fish Oils

• Numerous preparations—not subject

to same regulatory and manufacturing

oversight by the FDA

• EPA and DHA content per

recommended serving can vary

• Accuracy of the stated amount of EPA

and DHA can vary

• Concentrations of EPA and DHA

range from 20%-80% and may require

≥11 servings for TG-lowering efficacy

Bradberry JC, Hilleman DE. P T. 2013;38(11):681-691.



-3 FA: Phospholipid Form


• Krill oil

– Processed from crustacean: Antarctic krill (Euphausia superba)

– Major part of EPA/DHA occurs naturally in phospholipid form

– Lower concentrations compared to OTC fish oils

EPA ~14% and DHA ~6.5%

– Different ratio of EPA:DHA compared to OTC fish oils

Krill oil: EPA:DHA ratio, ~2:1

OTC Fish oils: EPA:DHA ratio, ~1.12:1

– Marketing claims more effective than fish oil, but this is based on flawed interpretation of evidence

Lipid and Lipoprotein Effects

of -3 FA Preparations


• No direct comparisons of prescription

preparations– 4-g dose of each prescription -3 FA product

(± statins) has been evaluated in randomized,

placebo-controlled, double-blind, parallel-group

trials including patients with very high TG

Lipid Effects of Prescription

Omega-3 in TG >500 mg/dL

Olive Oil(N=216)

OMG3CA 2g(N=215)

OMG3CA 4g(N=216)

EVOLVE (EPA+DHA FFA)

LS Mean Change from Baseline (%)

MARINE (EPA EE)

Placebo

(N=75)

Icosapent ethyl 4g

(N=76)

PlaceboCorrected

(N=76)

Median Change from Baseline (%)

Placebo

(N=42)

OMG3EE4g

(N=42)

PlaceboCorrected

(N=42)

Median Change from Baseline (%)

EPA+DHA EE

LDL-C Δ +19.4%* +19.2%* +3% -4.5% -7.5% +3% +45%* +49.8% -4.8%

*P<0.05

**

* *

*

*

*

*

*

Kastelein JJP, et al. J Clin Lipidol. 2014;8:94-106.Bays HE, et al. Am J Cardiol. 2011;108:682-690.



Lipid and Lipoprotein Effects

of -3 FA Preparations: 4 g/day (TG 500-1500/200 mg/dL)

% vs

placebo

-3 FA EE

EPA + DHA

-3 FA EE

EPA + DHA

-3 FA EE

EPA

-3 FFA

EPA + DHA

N 84 254 229 399

TG -52

(P =NR)

-14

(P <.05)

-33

(P <.0001)

-21

(P <.001)

LDL-C +49

(P =NR)

+19

(P <.01)

-2

(P =NR)

+15

(P =NR)

HDL-C +9

(P =NR)

+5

(P =NR)

-4

(P =NR)

+4

(P =NS)

Non-HDL-C -10

(P =NR)

-9

(P =NR)

-18

(P =NR)

-10

(P <.01)

Apo B NR NR -9

(P <.05)

+2

(P =NR)


Statin + EPA/DHA EE (TG 200-500):

COMBOS Lipid Endpoints

Med

ian

ch

an

ge

fro

m b

aseli

ne (

%) TG LDL-C HDL-CVLDL-C

Additional changes to

baseline simvastatin therapy

P-OM3 EE 4 g/d + simvastatin 40 mg/d

Placebo + simvastatin 40 mg/d

5

–5

–10

–15

–20

–25

–30

3.4*

–6.3–7.2

–1.2–2.8

–29.5*

0.7‡

0

–27.5*

–4.2†

–1.9

Apo BNon–HDL-C

–9.0*

–2.2

*P<0.0001 between groups; †P=0.0232 between groups; ‡P=0.0522 between groups.

TG 200-500 baseline on statin.

Davidson MH, et al. Clin Ther. 2007;29:1354-1367.

P, prescription

EPA, eicosapentaenoic acid

DHA, docosahexaenoic acid

-25

-20

-15

-10

-5

0

Statin + EPA EE (TG 200-500): ANCHOR Lipid Endpoints

****P<.0001; ***P<.001; **P<.01; *P<.05;

NS = not significant (P≥.05), icosapent ethyl versus placebo

TG Non–HDL-C Apo B

Me

dia

n P

lac

eb

o-a

dju

ste

d C

ha

ng

e (

%)

LDL-C HDL-C

-21.5

****

-10.1

***

-13.6

****

-5.5

**

-9.3

****

-3.8

* -6.2

**

-3.6

NS-4.5

**

-2.2

NS

254265 8282128128 9193 3837 Baseline

(mg/dL)

4 g/day2 g/day

Icosapent Ethyl

12-week trial in high-risk statin-treated patients (n = 702) with TG 200-500 and LDL-C 40-100.

Ballantyne CM, et al. Am J Cardiol. 2012;110:984-992.



Lipid and Lipoprotein Effects of -3 FA

Preparations: 4 g/day (TG ≥200 to <500 mg/dL)

% vs placebo -3 FA EE

EPA + DHA +

statin

-3 FA EE

EPA + statin

-3 FFA

EPA + DHA +

statin

N 254 453 418

TG -23

(P<.0001)

-22

(P<.0001)

-21 vs -6

(P<.001)

LDL-C +4

(P=.05)

-6

(P=.0067)

+1 vs +1

(P≥.05)

HDL-C +5

(P<.05)

-5

(P=.0013)

+3 vs +2

(P≥.05)

Non-HDL-C -7

(P<.0001)

-14

(P<.0001)

-7 vs -0.9

(P<.001)

Apo B -2

(P<.05)

-9

(P<.0001)

-2 vs +0.3

(P<.05)


Lipid and Lipoprotein Effects of -3 FA

Preparations: 4 g/day (TG ≥200 to <500 mg/dL)

% vs placebo -3 FA EE

EPA + DHA +

statin

-3 FA EE

EPA + statin

-3 FFA

EPA + DHA +

statin

N 254 453 418

TG -23

(P <.0001)

-22

(P <.0001)

-21 vs -6

(P<.001)

LDL-C +4

(P =.05)

-6

(P =.0067)

+1 vs +1

(P≥.05)

HDL-C +5

(P <.05)

-5

(P =.0013)

+3 vs +2

(P≥.05)

Non-HDL-C -7

(P <.0001)

-14

(P <.0001)

-7 vs -0.9

(P<.001)

Apo B -2

(P<.05)

-9

(P<.0001)

-2 vs +0.3

(P<.05)


• Bottom line: • EPA+DHA better for

↓TG & ↑HDL-C

• EPA better for ↓LDL-C,

↓Non-HDL-C, ↓Apo B

EPA, DHA, or Both?

Davidson MH. Curr Opin Lipidol. 2013;24:467-474.

• Both EPA and DHA lower triglycerides

– DHA only and EPA/DHA > EPA only

• EPA has negligible effect on LDL-C

• DHA may raise LDL-C, likely due to reduction

in apoC-III production

– Enhanced lipolysis and conversion of VLDL to LDL

– May explain greater TG-lowering effect of DHA

– Larger LDL particle size, increase in HDL-C



Davidson MH. Curr Opin Lipidol. 2013;24:467-474.

EPA, DHA, or Both?

• EPA and DHA modify the composition of VLDL particles differently in patients with severe hypertriglyceridemia.

• Both EPA and DHA decrease the triglyceride composition of VLDL, but DHA also enhances the lipolysis of VLDL, resulting in greater conversion to LDL that is larger in size, as well as increases in HDL-C.

ApoC-III Promotes Dyslipidemia and

Atherosclerosis

• Liver-derived apolipoprotein is present on TG-rich

lipoproteins and HDL

• Promotes HTG by inhibiting LPL and inhibition of apo E

binding to hepatic receptors

– Thus reducing lipolysis and clearance of TG-rich lipoproteins

• ApoC-III–containing LDL is more strongly associated with

CV risk than LDL without apoC-III

HDL

Chylomicronremnants

HDL

Apolipoprotein C-III has Significant

Consequences for Lipoprotein Metabolism

1. Ooi EM, et al. Clin Sci. 2008;114:611-624; 2. Caron S, et al. Arterioscler Thromb Vasc Biol. 2011;31(3):513-519;

3. Ginsberg HN, et al. Arterioscler Thromb Vasc Biol. 2011;31:471-473; 4. Sacks FM, et al. Circulation. 2000;102:1886-1892.

ABCA1

CEFC

ApoA-I

Nascent

ApoA-Idiscs

LCAT?

Mature

CEHL

TG

Macrophage

LPL

BileLDLr

SR-B1LSR

Liver

LPL

• ApoC−III modifies particle

composition1

– Inhibits the conversion of VLDL to

LDL

– Causes an increase in small, dense LDL and a decrease in

HDL−C

• Glucose increases apoC−III gene

expression and may link diabetes and TGs2

• ApoC−III-enriched LDL can increase monocyte binding to endothelial cells3

• ApoC−III in VLDL+LDL is a marker of increased risk of recurrent coronary events4

ApoC-III Effects

LDL

VLDL

Chylomicron

___

__ ApoC-III

IDL

LSR=lipolysis stimulated lipoprotein receptor; SR-B1=scavenger

receptor class B1; LCAT=lecithin-cholesterol acyltransferase;

CETP=cholesteryl ester transfer protein; LPL=lipoprotein lipase;

LDLr=low-density lipoprotein receptor.



Sacks FM, et al. Circulation. 2000;102:1886-1892.

CARE Trial

• ApoC-III in VLDL + LDL was a marker of

increased risk of recurrent coronary events

-11

-14

2

-20

-15

-10

-5

0

5

10

OMG3CA 2g OMG3CA 4g Olive Oil

Omega-3 Fatty Acids Containing EPA + DHA

Have Been Shown to Lower ApoC-III

LS

mean c

hange f

rom

baseline (

%)

*

***

P<.05* <.01** <.001***

EVOLVE (TG ≥500 mg/dL)

-8

-13

-3

-20

-15

-10

-5

0

5

10

OMG3CA 2g OMG3CA 4g Olive Oil

LS

mean c

hange f

rom

baseline (

%)

***

ESPRIT (TG 200-499 mg/dL)

-8

-10

-20

-15

-10

-5

0

5

10OMG3CA 2g OMG3EE 4g Corn oil

COMBOS

(TG 200-499 mg/dL)

***

Omega-3 Carboxylic AcidsOmega-3

Ethyl Esters

N=399 N=647 N=256

Omega-3 Carboxylic Acids

Kastelein JJ, et al. J Clin Lipidol. 2014;8:94-106.

Bradbury CJ, et al. Pharm Ther. 2013;38:681-691.

Koski RR. Pharm Ther. 2008;33:271-303.

OMG3CA: Omega-3 carboxylic acids

OMG3EE: Omega-3 ethyl esters

Reductions in ApoC-III Are

Associated with Omega-3 Products

-15

-10

-5

0

5

10

Baseline Day 45 Day 90

Ch

an

ge

(%

)

DHA 3 g/day Placebo

N= 17, 17

P<.01

DHA vs PBOEPA EE alone

Kelley DS, et al. Am J Clin Nutr. 2007;

86:324-333.

0

5

10

15

20

25

30

% reductionapoC-III vs.

placebo

% reductionapoC-III vs.

placebo

EPA EE 2g EPA EE 4 g

Post-hoc analyses, MARINE (n=148)

(TG ≥500 mg/dL) and ANCHOR

(n=612) (TG 200-499 mg/dL)

Unpublished data, Ballantyne, NLA

May 2014



Summary: -3 FA

• Insufficient evidence regarding clinical implications of short-

and long-term bioavailability of different formulations of -3 FA

– TG vs EE vs FFA vs PL?

• EPA and DHA both have TG-lowering effects

• DHA may raise LDL-C due to enhanced lipolysis

– Increase in LDL particle size, increase in HDL-C

• EPA and omega-3 fatty acid products that contain DHA lower

apoC-III

Summary: -3 FAs

• OTC fish oil preparations are not regulated by the

FDA and may vary in consistency of concentrations

of EPA and DHA

• Krill oil preparations have lower concentrations of

-3 FAs and may require greater number of

capsules to achieve maximum/adequate TG-

lowering benefits

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