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
1
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
2
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
4
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. 6673 3. 7479 4. 8087 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
7
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
9
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
17
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
19
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%)
>12/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 24 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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