Wading through the Sea
of Fish Oil Choices:
Separating Science from
Marketing
What comprises the fats we speak so
much abo...
Disclosures
• Formulator of VitalOils1000
• Treasurer of ISSFAL
Today’s Goals
• Critical Definitions
• Properly read a Fish Oil Label
• Understand EPA, DHA, and their

derivatives
• Revi...
Definitions
•
•
•
•
•
•

Triglycerides
Absorption of TGs
Diglycerides
Phospholipids
Saturated vs. Unsaturated Fatty Acids
...
Triglycerides
• More properly known as Triacylglycerol
• Glycerol (an alcohol) is esterified with

three Fatty Acids (whic...
Glycerol – The
Backbone
Intestinal Absorption of TG
• Bile Acids act as soaps to emulsify fats
• Small fat globules result allowing water soluble
...
Diglyceride
Diacylglycerol (DAG)
Phospholipid
Phospholipids
• Class of lipids ESSENTIAL for membrane
•
•
•
•

function
Contain phosphate group and built upon
nitrogen-c...
The complexity of a cell
membrane
Saturation/Unsaturation of
Fatty Acids
• Saturated Fats contain the MAXIMUM # of
•
•
•

Hydrogen atoms and NO Double Bonds...
Saturated Fatty Acid
Unsaturated Fatty
Acid
Monounsaturated Fat
MUFA
• Oleic Acid
• Omega-9
• First DB in the ninth carbon position from
the end
• Olive Oil and Canol...
Oleic Acid
Cis vs. Trans:
Oleic vs. Elaidic Acids

Melting points 13.4 C vs. 43 C
Polyunsaturated Fatty Acids:
PUFAs
• PUFA’s (Omega 3,6,9) defined by the location of
•
•
•

the first DB, counting from th...
Linoleic Acid (LA): The 18 carbon
Omega-6 Essential Fatty Acid

LA 18:2 n-6
Number of
carbon atoms

Number of
double
bonds...
Alpha Linolenic Acid (ALA):
The 18 carbon Omega-3
Essential Fatty Acid

ALA 18:3 n-3
Number of carbon
atoms

Number of
dou...
Relationships Among the
PUFAs
• In general, the longer the chain (more carbon atoms)
and the less saturated (more DB) the ...
Linoleic Acid (LA 18:2 n-6)

EFAs

Alpha Linolenic Acid (ALA 18:3 n-3)

Desaturation

Gamma Linolenic Acid (GLA 18:3 n-6)
...
Omega-3s DHA and EPA: EE, TG,
FFA, and PL Forms
EPA, DHA, AND THEIR
DERIVATIVES:
WHY THESE FATS ARE SO
ESSENTIAL
Different Aspects of the Omega3s DHA and EPA
• DHA is preferentially taken up by cell

•
•
•
•

membranes to increase memb...
DHA Conformations

Dr. Scott Feller
Biologic Effects of EPA and
DHA
•
•
•
•
•

Triglyceride Lowering
Anti-arrhythmic
Anti-oxidant
Anti-inflammatory
Anti-throm...
Triglyceride - Lowering
• Both lower TG (8%/1000 mg)
• 4 Nuclear receptors influenced to decrease TG
•
•
•
•

production a...
Anti-arrhythmic effects
• Structural plasticity and free caboxyl group
•
•
•
•

are essential
Direct effects on several ch...
Anti-oxidant effects
• Decrease production of F2 Isoprostanes
• No increase in F3 and F4 Isoprostanes

Baum, Curr Cardiova...
Anti-inflammatory effects
• Multi-factorial
• Decrease intra-plaque IL6, T cells, MMPs,
ICAM-1
• N.B. IL6 is the only cyto...
Anti-thrombotic effects

• Doses < 5 gm/day do not increase
•
•
•
•

bleeding times
DHA&EPA incorporation into Platelet
ph...
Eicosanoids
• 20 carbon FA derivatives of AA and EPA
• Essential for homeostasis with respect to inflammation,
•

thrombos...
Classical Eicosanoids:
• Leukotrienes: Created by action of
lipoxygenases (LOX)
• Prostanoids: Created by action of
cycloo...
The Danger of Misguided
Manipulation of Eicosanoids:
The NSAIDS
• Basal state COX-1 predominates, protecting GI
•
•

tract...
The Danger of Misguided
Manipulation of Eicosanoids,
Con’t
• Hypothesis: Selective COX-2 inhibition would

•

“kill 2 bird...
ASA, the Only NSAID to
Decrease CVD Events
• Only NSAID to Irreversibly block COX-1
• Results in nearly complete inhibitio...
Non-Classical Eicosanoids
EETs
• Derived from CYP 2C and 2J
• 4 EETs formed from AA and ALL are

vasculoprotective
• Short...
Non-Classical Eicosanoids
Lipoxins
• Formed from action of 12- and 15- LOX on
AA or EPA
• LXA4 is prototypical Lipoxin
–
–...
Non-Classical Eicosanoids
Resolvins
• As opposed to previous Lipoxins,

Resolvins are derived from ONLY
EPA&DHA
• EPA-Deri...
Non-Classical Eicosanoids
Resolvins Con’t
• Anti-inflammatory
• Inflammation-Resolving
• Suppress cytokine secretion and

...
Docosanoids
• DHA most abundant of LCPUFA omega-

3s
• DHA is particularly concentrated in neural
tissue
• Docosanoids are...
NPD1
•
•
•
•

Anti-angiogenic
Pro-homeostatic
Anti-inflammatory
Much of prior research on neural and
ocular disorders
• Fu...
Clinical Trials
• Observational Trials consistently showed
association of high fish intake with low
CVD and low fish intak...
Eight Large CVD Intervention
Trials
• Comparisons are difficult secondary to
design differences –
–
–
–
–

Time of interve...
1. DART: Diet And Reinfarction
Trial
• Randomized 2,000 men s/p MI.
• Three dietary advice interventions:

•

a.low-fat, i...
2. DART 2
• 3,000 male patients with angina and 4
dietary advice arms:
a.No advice
b.Increased fruits, vegetables, and oat...
3. GISSI-Prevenzione: The Gruppo Italiano
per lo Studio della Sopravvivenza
nell’Infarto Miocardico
• 11,000 patients with...
4. OMEGA: Germany
• OMEGA, a randomized, placebo-

controlled trial to test the effect of highly
purified omega-3 fatty ac...
OMEGA continued
•
•
•
•
•

a. 3,800 patients 3-14 days post-MI
B. 840 mg omega-3 vs. placebo (olive oil)
c. Primary endpoi...
5. Alpha Omega Trial:
Netherlands
• a. 5,000 patients with h/o MI within 10 years
•
•
•
•
•

(median 3.7 years)
b. 4 Trial...
Alpha Omega Trial: Continued
• g. Design flaws: Low dose omega-3s

EPA+DHA; high dose of ALA; long period
post-MI prior to...
6. SU.FOL.OM3 Study: Supplement with
Folic Acid and/or Omega-3 fatty Acids:
France
• a. 2,500 patients with coronary or ce...
7. ORIGIN: The Outcome Reduction
with Initial Glargine Intervention

• a. 12,500 patients with IGT or DM
• b. 2X2 Factoria...
8. JELIS: Japan EPA Lipid
Intervention Study

• a. 18,500 patients: 15,000 Primary and

3,500 Secondary Prevention
• b. Op...
JAMA Meta-analysis, Rizos et al
• September 2012: Association between omega-3

•
•

fatty acid supplementation and risk of...
JAMA (Con’t)
• c. Authors required a p value < 0.0063. If

conventional < 0.05 p value, results would
have been significan...
SCD vs. Non-fatal CVD Events
• Non-linear relationship of fish oil to SCD
• Approximately 250 mg/day is threshold to
decre...
Prostate Cancer - SELECT:
Brasky’s Blemishes
1. Don’t Ignore earlier positive trials: PHS, Harvard Trial,
2.
3.
4.
5.
6.

...
Guidelines
• AHA: 1,000 mg combined EPA+DHA in
•
•
•
•

CVD
AHA: Fatty fish > 2x/wk or 500 mg QD
EuroPRevent: “Regular con...
Final Thoughts
• In view of our Current Diet, EPA and DHA are
•
•
•

“Essential” Fats
EPA and DHA have myriad physiologic ...
Seth Baum, MD - Wading through the Sea of Fish Oil Choices; How do we Sort Science from Marketing
Seth Baum, MD - Wading through the Sea of Fish Oil Choices; How do we Sort Science from Marketing
Seth Baum, MD - Wading through the Sea of Fish Oil Choices; How do we Sort Science from Marketing
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  • Seth Baum, MD - Wading through the Sea of Fish Oil Choices; How do we Sort Science from Marketing

    1. 1. Wading through the Sea of Fish Oil Choices: Separating Science from Marketing What comprises the fats we speak so much about? And, do they truly help our Hearts? Seth J. Baum, MD, FACC, FAHA, FACPM, FNLA Director, Women’s Preventive Cardiology, BRRH
    2. 2. Disclosures • Formulator of VitalOils1000 • Treasurer of ISSFAL
    3. 3. Today’s Goals • Critical Definitions • Properly read a Fish Oil Label • Understand EPA, DHA, and their derivatives • Review the largest Omega-3 CVD Intervention Trials
    4. 4. Definitions • • • • • • Triglycerides Absorption of TGs Diglycerides Phospholipids Saturated vs. Unsaturated Fatty Acids Omega-3 Fatty Acids and Omega-6 Fatty Acids
    5. 5. Triglycerides • More properly known as Triacylglycerol • Glycerol (an alcohol) is esterified with three Fatty Acids (which can all be different) • The main constituent of vegetable oil and animal fat
    6. 6. Glycerol – The Backbone
    7. 7. Intestinal Absorption of TG • Bile Acids act as soaps to emulsify fats • Small fat globules result allowing water soluble • • • • Lipase to interact more effectively with fat Triglycerides are broken into Monoglycerides and Free Fatty Acids by Lipases Micelles transport these breakdown products into the enterocytes FFAs are absorbed directly Chylomicrons formed in enterocytes enter body through lymphatics
    8. 8. Diglyceride Diacylglycerol (DAG)
    9. 9. Phospholipid
    10. 10. Phospholipids • Class of lipids ESSENTIAL for membrane • • • • function Contain phosphate group and built upon nitrogen-containing alcohol Amphiphilic (Amphipathic) – head is hydrophilic while tail is lipophilic Integral part of Lipid Bilayer Phospholipids move laterally in membranes – essential for lipid polymorphism (how lipids aggregate)
    11. 11. The complexity of a cell membrane
    12. 12. Saturation/Unsaturation of Fatty Acids • Saturated Fats contain the MAXIMUM # of • • • Hydrogen atoms and NO Double Bonds – They are Saturated with Hydrogen Atoms Unsaturated Fats Lack two or more Hydrogen Atoms and thus have one or more Double Bond Mono-unsaturated Fats (MUFAs) have one DB Polyunsaturated Fats (PUFAs) have >1 DB
    13. 13. Saturated Fatty Acid
    14. 14. Unsaturated Fatty Acid
    15. 15. Monounsaturated Fat MUFA • Oleic Acid • Omega-9 • First DB in the ninth carbon position from the end • Olive Oil and Canola Oil
    16. 16. Oleic Acid
    17. 17. Cis vs. Trans: Oleic vs. Elaidic Acids Melting points 13.4 C vs. 43 C
    18. 18. Polyunsaturated Fatty Acids: PUFAs • PUFA’s (Omega 3,6,9) defined by the location of • • • the first DB, counting from the terminal carbon Omega-3 FA have their first DB in 3rd carbon position from the chain’s end Omega-6 FA have their first DB in 6th carbon position from the end Essential Fatty Acids LA and ALA were originally defined as Vitamin F in 1923
    19. 19. Linoleic Acid (LA): The 18 carbon Omega-6 Essential Fatty Acid LA 18:2 n-6 Number of carbon atoms Number of double bonds Position of the first double bond
    20. 20. Alpha Linolenic Acid (ALA): The 18 carbon Omega-3 Essential Fatty Acid ALA 18:3 n-3 Number of carbon atoms Number of double bonds Position of the first double bond
    21. 21. Relationships Among the PUFAs • In general, the longer the chain (more carbon atoms) and the less saturated (more DB) the more metabolically active the FA
    22. 22. Linoleic Acid (LA 18:2 n-6) EFAs Alpha Linolenic Acid (ALA 18:3 n-3) Desaturation Gamma Linolenic Acid (GLA 18:3 n-6) Stearidonic Acid (18:4 n-3) Elongation Dihomo- Gamma-Linolenic Acid (20:3 n-6) 20:4 n-3 Series 1 PG Desaturation Arachidonic Acid (AA 20:4 n-6) Eicosapentaenoic Acid (EPA 20:5 n-3) Cyclooxygenase/Lipoxygenase Prostaglandin 2 Series, Leukotrienes, Prostacyclins, Thromboxanes Series 3 PG Elongation/desaturation Docosahexaenoic Acid (DHA 22:6 n-3)
    23. 23. Omega-3s DHA and EPA: EE, TG, FFA, and PL Forms
    24. 24. EPA, DHA, AND THEIR DERIVATIVES: WHY THESE FATS ARE SO ESSENTIAL
    25. 25. Different Aspects of the Omega3s DHA and EPA • DHA is preferentially taken up by cell • • • • membranes to increase membrane fluidity, regulate gene expression, modulate ion channels, and enhance pinocytosis. DHA is the precursor for Docosanoids. EPA is used mostly as precursor for Eicosanoids. Conversion of ALA to EPA is approximately 10%, while conversion to DHA is only 1-2%. Retroconversion of DHA to EPA may be more prevalent than forward conversion. Trans fats further reduce conversion to DHA.
    26. 26. DHA Conformations Dr. Scott Feller
    27. 27. Biologic Effects of EPA and DHA • • • • • Triglyceride Lowering Anti-arrhythmic Anti-oxidant Anti-inflammatory Anti-thrombotic Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    28. 28. Triglyceride - Lowering • Both lower TG (8%/1000 mg) • 4 Nuclear receptors influenced to decrease TG • • • • production and increase degradation (LXR, HNF4 alpha, FXR, PPARs) SREBP 1c is impacted by all 4 LPL is increased Apo C3 is decreased VLDL production is decreased and Chylomicron clearance is increased Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    29. 29. Anti-arrhythmic effects • Structural plasticity and free caboxyl group • • • • are essential Direct effects on several channels Improved cell signaling from DHA incorporation in cell membrane Stabilize cardiac myocytes - lower resting membrane potential & prolong refractory period “Fuel” function Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    30. 30. Anti-oxidant effects • Decrease production of F2 Isoprostanes • No increase in F3 and F4 Isoprostanes Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    31. 31. Anti-inflammatory effects • Multi-factorial • Decrease intra-plaque IL6, T cells, MMPs, ICAM-1 • N.B. IL6 is the only cytokine known to influence ALL inflammatory acute phase reactants Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    32. 32. Anti-thrombotic effects • Doses < 5 gm/day do not increase • • • • bleeding times DHA&EPA incorporation into Platelet phospholipids leads to these effects: Decrease platelet activating factor (PAF) Down-regulate platelet-derived growth factors, A&B Indirectly reduce monocyte-derived thromboplastin and thromboxane B2 Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    33. 33. Eicosanoids • 20 carbon FA derivatives of AA and EPA • Essential for homeostasis with respect to inflammation, • thrombosis, endothelial function, vascular resistance Two groups: Classical (Prostanoids and Leukotrienes) and Non-classical (Lipoxins, Resolvins, EETs) – Prostaglandins (PG) – Prostacyclin (PG) – Thromboxanes (TX) – Leukotrienes (LT) Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    34. 34. Classical Eicosanoids: • Leukotrienes: Created by action of lipoxygenases (LOX) • Prostanoids: Created by action of cyclooxygenases (COX) Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    35. 35. The Danger of Misguided Manipulation of Eicosanoids: The NSAIDS • Basal state COX-1 predominates, protecting GI • • tract (protective PGs) and producing low levels of PGI2 Upregulation of COX-2 increases PGE2 but also makes PGI2 dominant Non-specific NSAIDS decrease pain, but increase GI bleeds by inhibiting COX-1 Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    36. 36. The Danger of Misguided Manipulation of Eicosanoids, Con’t • Hypothesis: Selective COX-2 inhibition would • “kill 2 birds with one stone”: by decreasing PGE2, decrease both pain and CVD. Also, no COX-1 inhibition so no GI SE Unfortunately, COX-2 inhibition also dramatically decreases PGI2. CV events increased as TXA2 became ”unopposed” by PGI2 • PG balance is delicate Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    37. 37. ASA, the Only NSAID to Decrease CVD Events • Only NSAID to Irreversibly block COX-1 • Results in nearly complete inhibition of platelets’ ability to produce TXA2 Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    38. 38. Non-Classical Eicosanoids EETs • Derived from CYP 2C and 2J • 4 EETs formed from AA and ALL are vasculoprotective • Short-lived as consequence of sEH (soluble Epoxide Hydrolase) • Potential for future drug development Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    39. 39. Non-Classical Eicosanoids Lipoxins • Formed from action of 12- and 15- LOX on AA or EPA • LXA4 is prototypical Lipoxin – – – – Anti-inflammatory Decrease Neutrophil chemotaxis Attenuate TNF� Antithesis of LTB4 (but made from same precursor!) Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    40. 40. Non-Classical Eicosanoids Resolvins • As opposed to previous Lipoxins, Resolvins are derived from ONLY EPA&DHA • EPA-Derived are Resolvin Es • DHA-Derived are Resolvin Ds • Sequential actions of 3 enzymes – CYP450, COX-2, LOXs Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    41. 41. Non-Classical Eicosanoids Resolvins Con’t • Anti-inflammatory • Inflammation-Resolving • Suppress cytokine secretion and Neutrophil infiltration • Block pro-inflammatory effects of TXs • Utilize receptors distinct from those for Lipoxins and “Resolve” Inflammation Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    42. 42. Docosanoids • DHA most abundant of LCPUFA omega- 3s • DHA is particularly concentrated in neural tissue • Docosanoids are derived from ONLY DHA – Maresins – Neuroprostanes – Neuroprotectin D1 (NPD1) Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    43. 43. NPD1 • • • • Anti-angiogenic Pro-homeostatic Anti-inflammatory Much of prior research on neural and ocular disorders • Future research - cardiovascular Baum, Curr Cardiovasc Risk Rep DOI 10.1007/s12170-012-0224-6
    44. 44. Clinical Trials • Observational Trials consistently showed association of high fish intake with low CVD and low fish intake with high CVD • Next came the Intervention trials
    45. 45. Eight Large CVD Intervention Trials • Comparisons are difficult secondary to design differences – – – – – Time of intervention relative to CVD Event Dose of Intervention Duration of Intervention Baseline PUFA intake
    46. 46. 1. DART: Diet And Reinfarction Trial • Randomized 2,000 men s/p MI. • Three dietary advice interventions: • a.low-fat, increased fiber diet b. increased n-3 fatty acids, either in the form of fatty fish (200 - 400 gm per week, providing 500800 mg n-3 fatty acids per day) or c. fish oil capsules (900 mg EPA+DHA per day) N-3 group had a 29% decreased mortality at 2 years secondary to decreased CHD Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989;2:757-761
    47. 47. 2. DART 2 • 3,000 male patients with angina and 4 dietary advice arms: a.No advice b.Increased fruits, vegetables, and oats c. Increased fish oil in one of two ways: two fatty fish meals per week or 3 fish oil pills daily • Study was negative but rife with flaws – intergroup differences in meds, diseases and compliance. Burr ML, Ashfield-Watt PA, Dunstan FD, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57:193-200
    48. 48. 3. GISSI-Prevenzione: The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico • 11,000 patients within 3 months of MI • 4 groups: n-3 fatty acids 840 mg daily; Vitamin E 300 mg QD; Both; Neither • At 3.5 years 15% reduction in composite endpoint of death, non-fatal MI, non-fatal CVA • At 3.5 years 21% reduction in total mortality • At 3.5 years 30% reduction in CVD mortality • Results primarily driven by 45% reduction in SCD seen by month 4 GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447–455
    49. 49. 4. OMEGA: Germany • OMEGA, a randomized, placebo- controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction • Patients were aggressively managed with combination drug therapy and intervention: 95% were catheterized and 80% had PCI. Also, about half of patients in both groups ate fatty fish several times a week Rauch B, Schiele R, Schneider S, et al. OMEGA, a randomized, placebo-controlled trail to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 2010;122:2152-2159
    50. 50. OMEGA continued • • • • • a. 3,800 patients 3-14 days post-MI B. 840 mg omega-3 vs. placebo (olive oil) c. Primary endpoint: SCD within 1 year of MI d. Secondary endpoint: Total mortality and nonfatal clinical events SCD Rate was 1.5% in both arms – unexpectedly low: thereby under powering trial. This, with high baseline fish intake and only one year f/u contributed to null results
    51. 51. 5. Alpha Omega Trial: Netherlands • a. 5,000 patients with h/o MI within 10 years • • • • • (median 3.7 years) b. 4 Trial Margarines: 400 mg EPA+DHA; 2 gm ALA; Both; Neither c. Primary endpoint: Major CV events d. Patients treated with aggressive medical management e. 3.5 year f/u – Major CV events in about 14% f. No difference among groups Kromhout D, Giltay EJ, Geleijnse JM, et al. N-3 fatty acids and cardiovascular events after myocardial infarction. N Eng J Med 2010;363:2015-2026
    52. 52. Alpha Omega Trial: Continued • g. Design flaws: Low dose omega-3s EPA+DHA; high dose of ALA; long period post-MI prior to enrollment. • h. Post-hoc: DM patients taking EPA+DHA had a statistically significant 50% reduction in death from coronary disease
    53. 53. 6. SU.FOL.OM3 Study: Supplement with Folic Acid and/or Omega-3 fatty Acids: France • a. 2,500 patients with coronary or cerebral events in the • • • prior year b. Primary outcome to prevent major cardiovascular events c. 4 Groups: B vitamins (5-methyltetrahydrofolate (560mcg), vitamin B-6 (3 mg) and B-12 (20mcg); EPA+DHA – 400 and 200 mg respectively; Both; Neither d. Null results: flaws: low dose, long time interval s/p initial event; lower than expected overall event rate,, underpowered Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega-3 fatty acids on cardiovascular diseases: a randomized placebo controlled trial. BMJ 2010;341:c6273
    54. 54. 7. ORIGIN: The Outcome Reduction with Initial Glargine Intervention • a. 12,500 patients with IGT or DM • b. 2X2 Factorial Design • c. 840 mg EPA+DHA or Placebo; and Insulin Glargine or Standard care • d. Primary outcome CV Death • e. 6 year follow up no benefit from n-3 FA The ORIGIN Trial Investigators. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-318
    55. 55. 8. JELIS: Japan EPA Lipid Intervention Study • a. 18,500 patients: 15,000 Primary and 3,500 Secondary Prevention • b. Open-label design: 1,800 mg EPA plus statin vs. Statin alone • c. Major Cardiovascular event was primary endpoint • d. At 4.5 years 19% reduction in primary endpoint driven by reduction in non-fatal events Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098
    56. 56. JAMA Meta-analysis, Rizos et al • September 2012: Association between omega-3 • • fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis a. “There is no evidence for routine use of omega-3 fatty acids” – direct expert quote/conclusion b. Dr. Arnett (president, AHA) comment to Reuters, “this closes the issue of omega-3's role in heart disease "
    57. 57. JAMA (Con’t) • c. Authors required a p value < 0.0063. If conventional < 0.05 p value, results would have been significant: fish oil did reduce cardiovascular death (p value of 0.01) • d. Authors excluded GISSI and JELIS • e. Patients were optimally treated, had CVD, got omega-3s for about 4 years, averaged 63 y.o. Very specific subset of patients.
    58. 58. SCD vs. Non-fatal CVD Events • Non-linear relationship of fish oil to SCD • Approximately 250 mg/day is threshold to decrease SCD • Japanese consume 10x EPA/DHA compared with USA; therefore fully protected against SCD. • Non-fatal CVD protection requires higher doses – NOT achieved in western trials
    59. 59. Prostate Cancer - SELECT: Brasky’s Blemishes 1. Don’t Ignore earlier positive trials: PHS, Harvard Trial, 2. 3. 4. 5. 6. Terry’s study Insignificant difference in plasma EPA+DHA PL between cancer and controls: 3.62% and 3.75% Association ≠ Cause: Reverse Causation more likely here Source of EPA and DHA not revealed (? Fish contaminants) Japanese consume 10x fish we do yet have 1/8 risk of prostate cancer Findings contradict biology of these PUFAs Brasky jnci.oxfordjournals.org
    60. 60. Guidelines • AHA: 1,000 mg combined EPA+DHA in • • • • CVD AHA: Fatty fish > 2x/wk or 500 mg QD EuroPRevent: “Regular consumption of fatty fish” ISSFAL: Minimum of 500 mg/day EPA+DHA ISSFAL: Pregnant/Lactating women > 200 mg DHA
    61. 61. Final Thoughts • In view of our Current Diet, EPA and DHA are • • • “Essential” Fats EPA and DHA have myriad physiologic effects Outcome data are limited and will likely remain so We must rely upon our understanding of physiology, molecular and cell biology, and nutrition to guide us. RCTs will not “save us” here.

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