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Role of OmegaOmega-3 Fatty Acids in Cardiovascular Disease Prevention Tara Dall, MD Advanced Lipidology Diplomate American Board Clinical Lipidology www.advlip.com Slide Source: Lipids Online www.lipidsonline.org

3 Types of Fat

Slide Source: Lipids Online www.lipidsonline.org

Slide Source: Lipids Online www.lipidsonline.org

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Fat effect on cholesterol  Saturated: most  LDL-C, some neutral  Trans Fatty Acids:  LDL-C and  HDL-C  Monounsaturated: Maintain or  LDL-C LDL C and 

or maintain HDL-C  Polyunsaturated: Must be balanced  need more omega-3:  Triglycerides,  LDL-C,

small dense LDL-P  most get too much omega-6 Slide Source: Lipids Online www.lipidsonline.org

The Potential Cardiovascular Benefits of Omega 3s (EPA and DHA)  • Antilipid  • Antiarrhythymic  • Antiatherogenic  • Antithrombotic  • Anti-inflammatory  • Antihypertensive

Slide Source: Lipids Online www.lipidsonline.org

Omega 3 Fatty Acid Therapy Key ingredient for therapeutic benefit is – Eicosapentaenoic (EPA, 20:5n-3) and – Docosahexaenoic acid (DHA, 22:6n-3) • Sources of EPA and DHA – Alpha linolenic acid (ALA, 18:3n-3) in the diet – EPA and DHA directly from the diet – Dietary supplements – Prescription omega-3 FA • To reduce CV events, the dose of omega-3 FA therapy is ~1 g of EPA + DHA/day • To lower TG levels, the dose of omega-3 therapy is ~4 g of EPA + DHA/day

Slide Source: Lipids Online www.lipidsonline.org

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Essential Fatty Acid Families ω-6 family H3C

ω-3 family H3C

COOH

C18:2 ω-6

C18:3 ω-3

Linoleic

• Corn Oil • Safflower Oil • Sunflower Oil

• Flaxseed Oil • Canola Oil • Soybean y Oil

H3C

H3C

C20:4 ω-6

COOH

-Linolenic

C20:5 ω-3

COOH

Arachidonic

H3C

C22:6 ω-3 More thrombotic and inflammatory metabolites

COOH

Eicosapentaenoic (EPA) COOH

Docosahexaenoic (DHA)

Less thrombotic and • Oily Fish • Fish Oil Capsules inflammatory metabolites Slide Source: Lipids Online www.lipidsonline.org

OmegaOmega-6 to Omega Omega--3 imbalance  American diet 16-20 times as much

omega-6 as omega-3. Cave men ranged from 1:1 to 5:1  World Health Organization (WHO) 

suggest 5:1 to 10:1 ratio for adults

Slide Source: Lipids Online www.lipidsonline.org

Omega--3 Omega  Plant omega-3 (ALA ) only 5-10% converted to

EPA and DHA  flax richest source  in small amounts, canola oil, walnuts, leafy

greens, soy foods  Animal omega-3 (DHA & EPA)  fatty fish (not fried) Salmon,

Trout, herring, canned mackerel, sardines, shrimp Slide Source: Lipids Online www.lipidsonline.org

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Cardiovascular Outcome Data for EPA and DHA

DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid.

Slide Source: Lipids Online www.lipidsonline.org

Omega--3 Fatty Acid Outcome Trials Omega Studies have shown the cardiovascular benefit of consuming

diets high in omega-3  Diet and Reinfarction Trial (DART)1  Lyon Diet Heart Study2  Indo-Mediterranean I d M dit Di Diett Heart H t Study St d 3 Studies have shown the cardiovascular benefit of ALA  Cardiovascular Health Study4  Family Heart Study5  Health Professionals Follow-up Study6  Multiple Risk Factor Invervention Trial7  Nurses’ Health Study8

ALA=alphalinoleic acid. 1. Burr ML et al. Lancet. 1989;2:757-61. 2. Leaf A. Circulation. 1999;99:733-5. 3. Singh RB et al. Lancet. 2002;360:1455-61. 4. Lemaitre RN et al. Am J Clin Nutr. 2003;77:319-25. 5. Djousse L et al. Am J Clin Nutr. 2003;77:819-25. 6. Ascherio A et al. BMJ. 1996;313:84-90. 7. Dolecek TA. Proc Slide Source: Lipids Online Soc Exp Biol Med. 1992;200:177-82. 8. Hu FB et al. Am J Clin Nutr. www.lipidsonline.org 1999;69:890-7.

Cumulative Incidence of Major Coronary Events %) (%

Japan EPA Lipid Intervention Study (JELIS) 4

–19% 3

Control

2 1 0

EPA

Hazard ratio = 0.81 (0.69–0.95) p = 0.011 0

1

2

3

4

5

Years

18,645 Japanese (70% women, mean age 61 years) randomized to statin alone or statin + EPA (1.8 g/d) and followed for 5 years Yokoyama M. Presented at American Heart Association Scientific Sessions, Dallas, Texas, 14 November 2005.

Slide Source: Lipids Online www.lipidsonline.org

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Change from baseline (%)

Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients Major CHD Events*

Event rate (%)

10 8

19% Reduction P 0 011 P=0.011

6

3.5

4

2.8

2 0

Statin

Lipid Effects Statin (n=9319) Statin + EPA 1.8 g (n=9326)

20 10 0 -10

P<0.0001

-20 -30

LDL-C

-40

TC

TG

*Sudden cardiac death, fatal and non-fatal MI, unstable angina, angioplasty, stenting, or CABG. CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; TC=total cholesterol. Yokoyama M et al. Lancet. 2007;369:1090-1098.

Slide Source: Lipids Online www.lipidsonline.org

Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS): Results (Primary and Secondary Prevention)  In patients with a history of coronary artery disease

(secondary prevention), major coronary events were reduced by 19% (P=0.048)  158 [8.7%] in EPA group  197 [10.7%] in control group

 In patients with no history of coronary artery disease

(primary prevention), major coronary events reduced by 18% (P=0.132)  104 [1.4%] in EPA group  127 [1.7%] in control group

EPA=Eicosapentaenoic acid. Yokoyama M et al. Lancet. 2007;369:1090–1098.

Slide Source: Lipids Online www.lipidsonline.org

Relative Risk of Sudden Cardiac Death and Blood OmegaOmega3 Levels: Physicians' Health Study 1

90% reduction in risk

Relative e Risk

0.8

p for trend = 0.001

0.6 0.4 0.2 0

Mean:

1

2

3

4

4.76

5.63

6.87

Blood Omega-3 FA (%) by Quartile

3.58

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

Slide Source: Lipids Online www.lipidsonline.org

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GISSI--Prevenzione: Time Course of Clinical Events GISSI >11,300 postpost-MI patients were given usual care with or without 850 mg EPA+DHA for 3.5 years

Probability

Total mortality reduced by 28% (p=0.027)

1.00

n-3 PUFA Control

0.99 0.98

0.59 (0.36–0.97) p=0.037

0.97

0.72 (0.54–0.96) p=0.027

0.96 0 95 0.95

Days

0

30

60

90

120

150

180

210

240

270

300

330

360

1.00

Probability

Sudden death reduced by 47% (p=0.0136)

0.99 0.98

0.47 (0.22–0.99) p=0.048

0.97

0.95

Days

0

30

60

90

n-3 PUFA Control

0.53 (0.32–0.88) p=0.0136

0.96 120

150

180

210

240

270

300

330

360

Slide Source: Lipids Online www.lipidsonline.org

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

n-3 Control

mg/dL

50 48 46 44 42 40 38

Total Cholesterol

155 150 145 140 135 130 125

mg/dL

mg/dL

230 225 220 215 210 205 200

mg/dL

GISSI-Prevenzione: Effects of 850 mg/d of EPA+DHA GISSIon Serum Lipids

170 165 160 155 150 145 140

HDL Cholesterol

n-3 Control 1

2

3 4 Months

5

6

LDL Cholesterol

n-3 Control

Triglycerides

n-3 Control 1

2

3 4 Months

5

6

Slide Source: Lipids Online www.lipidsonline.org

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

Omega-3 FA and Risk for VT/VF in Patients Omegawith ICDs NO BENEFIT  200 patients with ICD and a

recent history of sustained VT or VF

 1.3 g/d EPA+DHA vs. placebo  2-year 2 f ll follow-up  Endpoint: time to first ICD

therapy for arrhythmia

 60% with class III/IV HF  None taking anti-arrhythmic

BENEFIT  402 with ICD implanted for

cardiac arrest or sustained VT/VF

 2.6 g/d EPA+DHA vs. placebo  1-year follow-up  Endpoint: time to first ICD

therapy or death

 15% with class III/IV HF  35% taking anti-arrhythmic drugs

drugs

Raitt MH et al. JAMA 2005;293:2884-2891. | Leaf A et al. Circulation 2005;112:27622768. Slide Source: Lipids Online www.lipidsonline.org

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Effect of EPA+DHA (810 mg/d  4 mo) on Heart Rate in 18 CHD Patients

bp pm

90

*74 vs 69 bpm, p<0.0001

85 80 75 70 65 60 55 50

Placebo

Omega-3 Supine

0

Standing

Sitting at rest

10

20

30

40

50

60

70

Minutes Slide Source: Lipids Online www.lipidsonline.org

O’Keefe JH Jr et al. Am J Cardiol 2006;97:1127-1130.

Heart Rate and Risk for Sudden Cardiac Death: Framingham Heart Study Biennial Age-adjusted Rate per 1000

6

***Men

***p<0.001

5.9

4.7

5 4

3.1 2 2.5

3 2 1

0.6

Women

0.2

0

1

1.8

1.5

1.5

1.1

2

3

4

Quintiles: 1. ≤65 2. 6673 3. 7479 4. 8087 5. ≥88

5

Quintile of Heart Rate Slide Source: Lipids Online www.lipidsonline.org

Kannel WB et al. Am Heart J 1985;109:876-885.

Omega-3 FA and Plaque Stability: OmegaPlaque Characteristics Control 80

Omega-3

Omega-6

* *

70

*p<0.05

Percentt

60 50 40

* *

* *

30

 Patients awaiting carotid endarterectomy (n=188) were randomized to control, fish oil (omega-3), or sunflower oil (omega-6) supplementation for median 34, 46, and 43 days preprocedure

 Plaques in omega-3 patients appeared to be more stable

20 10 0

IV

V AHA Type

VI

Theis F et al. Lancet 2003;361:477-485.

Thin Cap Slide Source: Lipids Online www.lipidsonline.org

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Data for Secondary Prevention in Patients With Heart Failure♦

Slide Source: Lipids Online www.lipidsonline.org

GISSI--HF: Design♦ GISSI Prospective, multicenter, randomized, double-blind, placebo-controlled, parallel assignment

P- OM3 1 g/day

Randomization 1 Patients with NYHA Class IIII–IV IV heart failure (n=~7000)

Placebo Rosuvastatin 10 mg/day

Randomization 2 Patients with NYHA Class II–IV heart failure and eligible for statin therapy (n=~5250)

Placebo

Concomitant therapy: all treatments proven effective for the treatment of heart failure (ACE inhibitors, beta-blockers, diuretics, digo spironolactone, amiodarone, aspirin, and/or oral anticoagulants). ACE=angiotensin-converting enzyme; GISSI-HF=Gruppo Italiano p Studio della Sopravvivenza Slide Source: nell’Infarto Miocardico Heart Failure Study; NYHA=New York Heart Lipids Online Association. www.lipidsonline.org Tavazzi L et al. Eur J Heart Fail. 2004;6:635–641.

GISSI-HF: Results GISSIPrimary End Points♦ LOVAZA n=3494 (%)

Placebo n=3481 (%)

P value

Adjusted Hazard Ratio

All-cause mortality

End Point (Intention to treat)

27

29

0.041

All-cause mortality or hospitalization for CV causes  All-cause mortality

57

59

0.009

0.91 (95% CI 0.833-0.998) 0.92 (99% CI 0.849-0.999) 0 849 0 999)

  

Absolute risk reduction of 1.8% Number needed to treat=56 for ~4 years Per protocol population (n=4994)  LOVAZA 26% versus placebo 29%  Adjusted hazard ratio (95% CI) =0.86 (0.77-0.95) P=0.004

 All-cause mortality or CV hospitalization  

Absolute risk reduction of 2.3% Number needed to treat=44 for ~4 years CI=confidence interval; CV=cardiovascular; GISSI-HF=Gruppo Italiano per Slide lo Source: Studio della Sopravvivenza nell’Infarto Miocardico Heart Failure Study. Lipids Online www.lipidsonline.org GISSI-HF Investigators. Lancet. In Press.

8


GISSI-HF: Results GISSISecondary End Points♦ End Point

Death from CV causes Sudden cardiac death Hospitalized Hospitalized for CV causes Hospitalized for heart failure Death from CV cause or hospitalization for any reason Fatal and non-fatal MI Fatal and non-fatal stroke

LOVAZA, n=3494 (%)

Placebo, n=3481 (%)

Adjusted hazard ratio (95% CI)

20.4 8.8 56.8 46.8 28.0 61.7

22.0 9.3 58.3 48.5 28.6 63.3

0.90 (0.81–0.99) 0.93 (0.79–1.08) 0.94 (0.88-1.00) 0.93 (0.87–0.99) 0.94 (0.86-1.02) 0.94 (0.89-0.99)

3.1 3.5

3.7 3.0

0.82 (0.63–1.06) 1.16 (0.89–1.51)

CI=confidence interval; CV=cardiovascular; MI=myocardial infarction; GISSI-HF=Gruppo Italiano per lo Studio della Slide Source: Sopravvivenza nell’Infarto Miocardico Heart Failure Study. Lipids Online GISSI-HF Investigators. Lancet. In Press. www.lipidsonline.org

GISSI--HF: Summary♦ GISSI  Long-term administration of Prescription Omega 3

1 g/day reduced all-cause mortality and hospitalizations for CV reasons in a large population of patients with heart failure  In the context of usual care  Consistent across predefined subgroups  Supported by per-protocol analysis

 No significant adverse events CV=cardiovascular; GISSI-HF=Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico Heart Failure Study. Slide Source: GISSI-HF Investigators. Lancet. In Press. Lipids Online

www.lipidsonline.org

Over the counter vs Prescription Omega 3

Slide Source: Lipids Online www.lipidsonline.org

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Prescription OmegaOmega-3 Acid Ethyl Esters (Lovaza formally Omacor)

≥90% OmegaOmega-3 EPA 465 mg

DHA 375 mg

Other Omega-3 60 mg

Omega-6 80 mg Omega-7 and -9 80 mg Other FA 10 mg Slide Source: Lipids Online www.lipidsonline.org

Composition of Prescription Omega Omega--3 FA  Less than 90 mg of n-6, n-7, and n-9 fatty acids  Heavy metals not detectable  Dioxins and halogenated polycarbons not

detectable  No Trans fatty acids

Slide Source: Lipids Online www.lipidsonline.org

High Dose Omega 3 FA 4g/day for Hypertriglyceridemia

Slide Source: Lipids Online www.lipidsonline.org

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Elevated Triglycerides Increase CHD Risk 12

TGs are independently associated with premature familial CHD*

CHD Odd ds Ratio

10

11.4

8 6 4 2 1.2

1.0

0

<100

1.7

1.1

2.8

100-149 150-199 200-299 300-499 Serum Triglycerides (mg/dL)

500-799

*Triglyceride odds ratio adjusted for HDL-C; n=653 (Family History=early CHD), n=1029 (control).

Slide Source: Lipids Online www.lipidsonline.org

CHD=coronary heart disease; HDL-C=high-density lipoprotein cholesterol; TG=triglyceride. Hopkins PN et al. J Am Coll Cardiol. 2005;45:1003-1012.

Triglyceride Level Predicts CHD Risk Meta--Analysis of 29 Studies (N = Meta 262,525) Groups

CHD Cases

Duration of follow-up ≥10 years <10 years Sex Male F Female l Fasting status Fasting Nonfasting Adjusted for HDL Yes No

CHD Risk Ratio* (95% CI)

5902 4256 7728

2674

1994 7484

4469 5689

Overall CHD Risk Ratio*

1.72 (1.56–1.90) Decreased Risk

1

Increased Risk

2

*Individuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid Slide Source: concentrations, and blood pressure (most). Lipids Online CHD=coronary heart disease. www.lipidsonline.org Sarwar N et al. Circulation. 2007;115:450-458.

Lipid and Lipoprotein Metabolism in the Normal Person Cholesteryl ester

Glycerol

Apo B

DGAT2

Triglyceride

VLDL (Very–low‐density lipoprotein) TG:Cholesterol=5:1 ratio

Fatty acids

Liver

Slide Source: Lipids Online www.lipidsonline.org

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Lipid and Lipoprotein Metabolism in the Normal Person Muscle and adipose tissue

Fatty acids

Lipoprotein lipase

Lipase

Bloodstream

LDL IDL

LDL receptor

VLDL Hepatocyte

Liver

Slide Source: Lipids Online www.lipidsonline.org

Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Increased triglyceride secretion Cholesteryl  ester

VLDL Triglycerides

TG:Cholesterol 5:1

Liver

Slide Source: Lipids Online www.lipidsonline.org

Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Muscle and adipose tissue Lipoprotein lipase

Lipase

Bloodstream

LDL

Decreased  conversion  to LDL

VLDL Liver

Slide Source: Lipids Online www.lipidsonline.org

12


Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Lipase

Bloodstream

LDL

↑ Small, dense LDL

IIncreased d VLDL

Rapid degradation Small, dense HDL

HDL Lipase

↓ HDL

Liver

↑ Free fatty acids ↑ Triglycerides ↑ Apo‐B

Slide Source: Lipids Online www.lipidsonline.org

NCEP Guidelines: Patient Types Based on Fasting Triglyceride Levels Patient Type (category)

Fasting TG Level (mg/dL)

Very high

500

High

200-499

Borderline high

150-199

Normal

<150

• Continue TLC even if lipid-lowering drug therapy is started NCEP=National Cholesterol Education Program; TG=triglyceride; TLC=therapeutic lifestyle changes. Slide Source: NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Lipids Online www.lipidsonline.org Report Executive Summary. 2001; NIH Publication No. 01-3670.

NCEP Guidelines: Treatment Objectives for Elevated Triglycerides Primary Objective

“Very High” TG ≥500 mg/dL “High” TG 200-499 mg/dL

↓ TG LDL goal

Secondary Objective

↓ LDL-C & non–HDL-C ↓ non–HDL-C (VLDL-C*, LDL-C)

*VLDL-C levels are influenced by triglyceride levels. HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; NCEP=National Cholesterol Education Program; TG=triglyceride; VLDL-C=very–low-density lipoprotein cholesterol. Slide Source: NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Lipids Online www.lipidsonline.org Third Report Executive Summary. 2001; NIH Publication No. 01-3670.

13


Pharmacologic Treatment Options for Triglyceride Reduction

   

Omega 3 Statins Fibrates Niacin Slide Source: Lipids Online www.lipidsonline.org

Prescription Omega 3 (Lovaza (Lovaza® )for Triglyceride Lowering  The effects of 4 g of Lovaza per day were assessed in two

randomized, placebo-controlled, double-blind, parallelgroup studies  84 adult patients (42 on Lovaza, 42 on placebo) with very

high triglyceride levels  Patients whose baseline triglyceride levels were between

500 and 2000 mg/dL were enrolled in these two studies of 6 and 16 weeks’ duration

Harris WS et al. J Cardiovasc Risk 1997;4:385-391. | Pownall HJ et al. Atherosclerosis 1999;143:285-297.

Slide Source: Lipids Online www.lipidsonline.org

Omega-3 Ethyl Esters and Lipid Levels in Patients with OmegaTriglycerides >500 mg/dL Baseline (mg/dL)

TG 816

NonHDL-C 27

HDL-C 22

60% 40% 20%

P<0.0001

P=0.0015 P=0.0002

6.7

0%

0.0

-45.0

Placebo

P<0.0001

LDL-C 89 P<0.0001 45.0

9.1 -0.9

-1.7 -13.8

-40%

VLDL-C 175

P=0.0059

-3.6

-20%

-60%

Chol 296

-4.8

-9.7

-42.0

Omega-3 Acid Ethyl Esters (4 g/day)

Pooled analysis: Harris WS et al. J Cardiovasc Risk 1997;4:385-391. | Pownall HJ et al. Atherosclerosis 1999;143:285-297.

Slide Source: Lipids Online www.lipidsonline.org

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Why Can Treatment With LOVAZA Increase LDL--C, and What Is the LDL Clinical Significance?

Slide Source: Lipids Online www.lipidsonline.org

Normalizing Lipid and Lipoprotein Metabolism Muscle and adipose tissue Lipoprotein lipase

Lipase

Bloodstream

Proper conversion to LDL

LDL

VLDL Liver Slide Source: Lipids Online www.lipidsonline.org

LDL-C Shifts Are Not Specific to Treatment LDLWith POM3 LOVAZA

Gemfibrozil

4 g/day (n=15)

Change in n lipid concentrattion (%)

Mean Baseline 30

871

201

10 -10

1200 mg/day (n=13)

116

622

126

+34%

+30% -46% -37%

-40%

-39% -33%

122

-40%

-30 -50

TG

VLDL-C

LDL-C

TG

VLDL-C

LDL-C

• 12-week, randomized, double-blind, double-dummy trial • N=30 patients with TG levels between 356 and 2492 mg/dL LDL-C=low-density lipoprotein cholesterol; TG=triglyceride; VLDL-C=very–low-density lipoprotein cholesterol. Stalenhoef AF, et al. Atherosclerosis. 2000;153:129-38.

Slide Source: Lipids Online www.lipidsonline.org

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Addition of POM3 4 g/day in Patients With High Triglycerides Taking Simvastatin♦ LDL--C by Baseline LDLLDL LDL-C Tertile

Median change from ba aseline (%)

10

9.5

LDL-C Tertile 3

LDL-C Tertile 2

LDL-C Tertile 1

(31.7-80.3 mg/dL)

(82-98.7 mg/dL)

(99-145.3 mg/dL)

LOVAZA 4 g/day + simvastatin 40 mg/day

8 6

Placebo + simvastatin 40 mg/day

4 2 0 –2 –4 –6 –8

1.1 -0.9 -3.8

-4.5

-6.4 n=41

n=43

n=40

n=46

n=39

n=45

Eligible subjects included men and women with LDL-C levels ≤10% above their NCEP ATP III goal and with TG levels 200-499 mg/dL after an 8-week lead-in phase of diet and simvastatin 40 mg/day. Slide Source: Lipids Online www.lipidsonline.org

LDL-C=low-density lipoprotein cholesterol, TG=triglyceride. Data on file. GlaxoSmithKline.

POM3 4 g/day Significantly Decreased Non–HDL-C1,2

Median va alues (mg/dL)

350 300

271

-14 %

250

215 VLDL-C

200

LDL-C Goal in Patients With 0-1 Risk Factor*3

150 100

IDL-C

50

LDL-C

P=0.0013

0 Baseline

End of Therapy

*LDL-C goals vary based on risk factors. HDL-C=high-density lipoprotein cholesterol; IDL-C=intermediate-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; VLDL-C=very–low-density lipoprotein cholesterol. 1. Prescribing Information for LOVAZA. Slide Source: 2. Data on file, GlaxoSmithKline. Lipids Online 3. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). www.lipidsonline.org Third Report Executive Summary. 2001; NIH Publication No. 01-3670.

Adding POM3 4 g/day to Simvastatin Increased LDL Particle Size* Median change in LDL particle size from base eline (%)

Post-hoc Analysis of Median Change in LDL Particle Size

1.2 1

LOVAZA 4 g/day + simvastatin 40 mg/day

1.0†

Placebo + simvastatin 40 mg/day

08 0.8 0.6

0.51

†P=0.0066

between groups.

0.4 0.2 0

n=106

n=120

*Measured by nuclear magnetic resonance (NMR). LDL=low-density lipoprotein. Data on File, GlaxoSmithKline.

Slide Source: Lipids Online www.lipidsonline.org

16


Does Treatment With LOVAZA Affect Lipoprotein Lipoprotein--associated Phospholipase A2 (Lp (Lp--PLA2)?

Slide Source: Lipids Online www.lipidsonline.org

Lp--PLA2 Is Associated With Risk of CHD Lp WOSCOPS (2000) WHI (2001) ARIC LDL<130 mg/dL (2004) Rotterdam (2005) Mayo Heart Study (2005) KAROLA (2005) Intermountain Heart ((2006)) PROSPER (2006) PROVE-IT (2006) THROMBO (2006) CHS (2006) MALMO (2007) PEACE (2007) 0

1

2

3

4

Risk Ratio for CHD Events CHD=coronary heart disease; Lp-PLA2=Lipoprotein-associated Phospholipase A2. Corson MA, et al. Am J Cardiol. 2008;101(suppl):41F-50F.

Slide Source: Lipids Online www.lipidsonline.org

Me edian change (%)

0

-5

-4.7

-10

-12.8 -15

P=0.0002 between groups.

LOVAZA 4 g/day + simvastatin 40 mg/day Placebo + simvastatin 40 mg/day Eligible subjects included men and women with LDL-C levels ≤10% above their NCEP ATP III goal and with TG levels 200-499 mg/dL after an 8-week lead-in phase of diet and simvastatin 40 mg/day.

Median trreatment difference (%)

Adding LOVAZA 4 g/day to Statins: Change in Lp--PLA2♦ Lp 0

-5

-5.1 -7.9

-10

-11 All P<0.01*

-15 LOVAZA 4 g/day + atorvastatin 10 mg (week 0-8) LOVAZA 4 g/day + atorvastatin 20 mg (week 8-12) LOVAZA 4 g/day + atorvastatin 40 mg (week 12-16) Eligible subjects included men and women with fasting non– HDL-C >160 mg/dL and TG ≥250 mg/dL and ≤599 mg/dL.

*P-value=Difference in median % change from baseline between LOVAZA plus atorvastatin and respective placebo plus atorvastatin groups. HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; Lp-PLA2=lipoprotein-associated phospholipase A2; TG=triglyceride. Data on file, GlaxoSmithKline.

Slide Source: Lipids Online www.lipidsonline.org

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AHA Recommendations for OmegaOmega-3 FA Intake Population

Recommendation

Patients without documented CHD

Eat a variety of (preferably oily) fish at least twice a week. Include oils and foods rich in -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

4 grams of EPA+DHA per day provided as capsules under a physicians care

Slide Source: Lipids Online www.lipidsonline.org

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

Fish as a Source of OmegaOmega-3 Fatty Acids 

Fish consumption1  Risk of heavy metal contaminants  Risk of other environmental contaminants

The FDA recommends no more than 12 ounces of low-mercury fish/week2 Type of fish

Approximate ounces needed to equal LOVAZA 4 g/day1

Tuna (light, (light canned, canned drained) Mackerel Pacific cod

Calories per serving3

40

1325

6.7–29

497–2151

77

2290 691–3970

Lobster

25–143

Scallop

59

1466

Salmon (Atlantic, farmed)

5-8

291–466

Catfish (farmed)

67

2842

The intakes of fish given above are very rough estimates because oil content can vary markedly (>300%) with species, season, diet, and packaging and cooking methods. 1. Kris-Etherton PM et al. Circulation. 2002;106:2747-2757. 2. U.S. Department of Health and Human Services and U.S. Environmental Protection Agency Consumer Advisory. Available at: http://www.fda.gov/bbs/topics/news/2004/NEW01038.html. Accessed August 7, 2008. Slide Source: 3. U.S. Department of Agriculture, Agricultural Research Service. 2007. USDA National Nutrient DatabaseLipids for Standard Reference, Online Release 20. Nutrient Data Laboratory Home Page. Available at: http://www.ars.usda.gov/nutrientdata.www.lipidsonline.org Accessed September 16, 2008.

Ways to Get 1 g/d EPA+DHA  Fish

- 2–3 oz salmon, sardines, mackerel per day  Dietary Supplements

- Low Potency: 300 mg EPA+DHA/g (Typical drug store capsules; 3 g/d) 500–700 700 mg EPA+DHA/g - Mid Potency: 500 (Mail-order, online, etc; 2 g/d  Drugs

- High Potency: 850 mg EPA+DHA/g (Omega-3 acid ethyl esters; 1 g/d)  Cod Liver Oil

- 1 tsp (RDA for vitamin D; 2 RDA for vitamin A) Slide Source: Lipids Online www.lipidsonline.org

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Summary • High TG levels are associated with atherogenic dyslipidemia and CHD and very high TG levels are associated with pancreatitis. • Treatment options for high TG include the following: – TLC for weight reduction/control – Statins to achieve LDL-C goal – Addition of fibrates, niacin, or fish oils to achieve non–HDL-C goal – Omega-3 FA therapy 1 g/day is an option for CHD patients • Treatment options for very high TG include the following: – TLC for weight reduction/control – Fibrates, niacin, and/or fish oils for TG lowering • Availability of a prescription grade omega 3-FA with consistent quality should prove to be useful for the medical management of TG-related disorders Slide Source: Lipids Online www.lipidsonline.org

Potential TriglycerideTriglyceride-Lowering Mechanisms of Omega--3 FA Omega Hormone-Sensitive Lipase

Adipose TG

Cell membrane

+

В-oxidation Mitochondria CPT-I, -II Acyl-CoA dehydrogenase

NEFA Glucose Uptake

FA Uptake

Acyl-CoA Acyl CoA

Acyl-CoA synthase

FA

Acetyl-CoA carboxylase FA synthase

Lipogenesis

Acetyl CoA

+ Β-oxidation DAG Glycerol-3-P

PA

Lyso PA

+ Peroxisome

PAP

Phospholipids

Acyl-CoA oxidase (rodents only?)

Harris WS and Bulchandani D. Curr Opin Lipidol 2006; 17:387-393.

DGAT

TG

VLDL

– Apo B-100

+ Degradation Slide Source: Lipids Online www.lipidsonline.org

Should blood omega omega--3 fatty acid levels be considered as a potential risk factor for sudden cardiac death?

If so, what would highhigh- and lowlow-risk levels be?

Slide Source: Lipids Online www.lipidsonline.org

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Risk for Primary Cardiac Arrest and Red Blood Cell EPA+DHA Level 1.0

90% reduction in risk

Odds R Ratio

0.8 0.6

*p<0.05 vs Q1

0.4 0.2 0.0

3.3%

4.3%

5.0%

6.5%

Mean RBC EPA+DHA by Quartile Adapted from Siscovick DS et al. JAMA 1995;274:1363-1367.

Slide Source: Lipids Online www.lipidsonline.org

Omega--3 Index Omega A measure of the amount of EPA+DHA in red blood cell membranes expressed as the percent of total fatty acids

There are 64 fatty acids in this model membrane, 3 of which are EPA or DHA 3/64 = 4.6% Omega-3 Index = 4.6% Harris WS et al. Prev Med 2004;39:212-220.

Slide Source: Lipids Online www.lipidsonline.org

Omega-3 Index (%)

Relationship Between Reported Intake of Tuna and Other NonNon-fried Fish and the OmegaOmega-3 Index (n=163) 12 10 8 6 4 2 0

<1/mon (13%)

>12/wk 1–3/mon 1/wk >2/wk (42%) (18%) (15%) (12%) Frequency of Intake (% of Population)

Sands SA et al. Lipids 2005;40:343-347.

Slide Source: Lipids Online www.lipidsonline.org

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Omega--3 Index: Study Estimates Omega Greatest Protection

GISSI-P:~9–10%

10%

CHS: 8.8% DART:~8–9%

8%

SCIMO: 8.3% 6%

Least Protection

4%

PHS: 3.9%

8.1%

5 epii studies:~8% t di 8% PHS: 7.3%

SCIMO: 3.4%

Seattle: 6.5%

Seattle: 3.3%

2%

Slide Source: Lipids Online www.lipidsonline.org

Harris WS et al. Prev Med 2004;39:212-220.

Proposed OmegaOmega-3 Index Risk Zones: Relative Risk for Death from CHD

Undesirable

0%

Intermediate

4%

Desirable

8%

10%

Percent of EPA + DHA in RBC

Slide Source: Lipids Online www.lipidsonline.org

Harris WS et al. Prev Med 2004;39:212-220.

The Omega Omega--3 Index: How Does It Compare with Traditional CHD Risk Factors? Physicians’ Health Study Relative Risk for Sudden Cardiac Death by Risk Factor 1.20

<0.001

0.98

0.37

0.56

.017

0.87

0.06

P for

<0.001 trend

RR SC CD

1.00

Q1 Q2 Q3 Q4

0.80 0.60 0.40 0.20 0.00

CRP

Hcy

TC

LDL

HDL

TG

TC/ HDL

ω-3 FA

Albert CM et al. Circulation 2002;105:2595-2599. | Albert CM et al. N Engl J Slide Source: Med 2002;346:1113-1118. Lipids Online

www.lipidsonline.org

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Omega--3 and CHD: Summary Omega  EPA and DHA have cardioprotective properties; effects of ALA are

unclear

 Mechanisms of action

- TG lowering: via a combination of inhibited hepatic TG synthesis/secretion and enhanced VLDL-TG clearance - Reduced risk for sudden cardiac death: via an increased resistance to ischemia-induced ventricular arrhythmias y  The Omega-3 Index (RBC EPA+DHA) has the potential to be a new risk

factor for CHD death

 AHA-recommended intakes range from 2 (preferably oily fish)

meals/wk (1° prevention), to ~1 g/d (2° prevention), to 24 g/d (triglyceride lowering)

 Omega-3 FA may be obtained from oily fish, cod liver oil, dietary

supplements, and a pharmaceutical preparation

Slide Source: Lipids Online www.lipidsonline.org

Tara Dall, MD Diplomate, American Board Clinical Lipidology Advanced Lipidology D l fi ld WI Delafield, www.advlip.com

Slide Source: Lipids Online www.lipidsonline.org

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