Seth Baum, MD - Wading through the Sea of Fish Oil Choices; How do we Sort Science from Marketing
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
4. 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
6. 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
9. Intestinal Absorption of TG
• Bile Acids act as soaps to emulsify fats
• Small fat globules result allowing water soluble
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•
•
•
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
12. 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)
14. 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
20. 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
21. 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
22. 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
23. 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
27. EPA, DHA, AND THEIR
DERIVATIVES:
WHY THESE FATS ARE SO
ESSENTIAL
28. 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.
30. 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
31. 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
32. 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
33. 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
34. 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
35. 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
36. 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
37. 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
38. 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
39. 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
40. 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
41. 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
42. 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
43. 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
44. 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
45. 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
47. 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
48. Eight Large CVD Intervention
Trials
• Comparisons are difficult secondary to
design differences –
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–
–
–
Time of intervention relative to CVD Event
Dose of Intervention
Duration of Intervention
Baseline PUFA intake
49. 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
50. 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
51. 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
52. 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
53. OMEGA continued
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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
54. 5. Alpha Omega Trial:
Netherlands
• a. 5,000 patients with h/o MI within 10 years
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(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
55. 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
56. 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
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•
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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
57. 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
58. 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
59. 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 "
60. 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.
61. 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
62. 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
63. Guidelines
• AHA: 1,000 mg combined EPA+DHA in
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•
•
•
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
64. 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.