Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
Eliot A. Brinton, MD, FAHA, FNLA, FACEPast-President, American Board of Clinical Lipidology
President, Utah Lipid CenterSalt Lake City, UT, [email protected]
11th Annual Orange County Symposium on Cardiovascular Disease Prevention
9 November 2019Orange, CA
Are All Omega-3 Agents
Similar for ASCVD Prevention?
Disclosures: Duality of Interest
Dr. Brinton has received:
• Research support from Amarin and Kowa
• Honoraria as consultant/advisor: Akcea, Amarin, Amgen, AstraZeneca, Esperion, Kowa, Regeneron and Sanofi-Aventis
• Honoraria as speaker: Amarin, Amgen, Kowa, Regeneron and Sanofi-Aventis
Omega-3 Talk Outline
• Dietary Supplement omega-3
• Omega-3 Acid Ethyl Esters (O3AEE, Lovaza)
• Icosapent Ethyl (pure EPA, Epadel & Vascepa) – JELIS
– REDUCE-IT
• Omega-3 Carboxylic Acid (O3CA, Epanova)– STRENGTH
• Summary and Conclusions
Purification of Omega-3: Dietary Supplements
Background: Omega-3 Dietary Supplements
• Fish oil is among the most commonly used dietary supplement among US
adults1
– Global market is expected to reach $3.3 billion by 20202
• Based on the 2012 National Health Interview Survey, ~7.8% of adults (19
million) had taken a fish oil supplement in the previous 30 days3
• Although numerous dietary supplements containing
Omega-3s are widely available, their integrity and efficacy remain unverified4
1. Barnes PM et al. National Health Statistics Reports. 2008;12:1-24.
2. http://globenewswire.com/news-release/2014/10/28/677161/10104781/en/Global-Fish-Oil-Market-By-Application-
Aquaculture-Direct-Human-Consumption-Is-Expected-to-Reach-USD-3-300-0-Million-by-2020-New-Report-By-
Grand-View-Research-Inc.html?parent=676724#sthash.GIGle3SR.dpuf
3. NIH NCCIH. Available at: https://nccih.nih.gov/health/omega3/introduction.htm
4. Mason RP et al. Poster presented at the AMCP 2015 Nexus. Orlando, FL.
Fish Oil Dietary Supplements Are Widely Used
• Not over-the-counter but unregulated dietary supplements
• Estimated global market for omega-3 products was $31 billion in 2015
• In a large UK prospective study, 31% of adults reported taking fish oils
• Estimates suggest 7.8% of US population (19 million people) take fish
oil supplements
• Benefits claimed on the heart, brain, weight, vision, inflammation, skin,
pregnancy and early life, liver fat, depression, childhood behavior,
mental decline, allergies, bones…
• Most common dietary supplements report 15-80% of their
contents as omega-3s– Most common is ~30%
• Assumption: each 1 gram capsule contains 300 mg of
EPA/DHA – In order to reach 4 g/day of ω-3s, a patient would need 3 to 7 times as
many capsulesHigh-potency
Rx ω-3 FA (4)1.0 g fill EPA + DHA
Dietary Supplement (13)
0.5 g fill EPA + DHA
Dietary Supplement (27)
Mason RP et al. Poster presented at the AMCP 2015 Nexus. Orlando, FL
0.3 g fill EPA + DHA
Krill Oil Dietary Supplement (44)
How Much EPA/DHA Is in a Dietary Supplement Omega-
3?
37%30%
21% 12%21%
36%34%
9%
Leading Fish Oil Supplement Leading Krill Oil Supplement
These chromatography findings have been noted by R. Preston Mason, PhD (unpublished data, 2015).
Saturated Fats
Unsaturated Fats
EPA
DHA
Fatty Acid Content of Leading Fish and Krill Oil
Supplements
21%
Fish oil dietary supplement
forms solid mass
Rx ω-3 is a clear fluid
High Saturated Fat Content in Dietary Fish Oil
Supplement Leads to Solid Mass Following Hydrolysis
Courtesy of Preston Mason, PhD.
Capsules were sliced open, contents crushed, and placed into vials
1 gm of ω-3 from
fish oil supplement
can include up to
1/3 of saturated fat
minimum daily
requirement
Peroxide, Anisidine, and TOTOX Values Measured in Rx and
Leading Dietary Supplements (DS)
*Global Organization for EPA and DHA Omega-3s (GOED). Available at: http://www.goedomega3.com/index.php
Mason RP et al. Poster presented at the AMCP 2015 Nexus. Orlando, FL.
Dietary Supplements
DS 1 DS 2 DS 3 DS 4
80
60
0
40
20
PV
(med/L
)
80
60
0
40
20Anis
idin
e
Valu
e
100
200
150
0
100
50
TO
TO
X
Va
lue
250
Normalized to Rx ω-3 FA
GOED standard*
<5 mEq/kg
<20 mEq/kg
<26 mEq/kg
Rx
Peroxide value (PV) measures
current oxidation
Anisidine value (AV) is a
measurement of past oxidation
TOTOX is total oxidation value,
past and present
1. US Food and Drug Administration. www.fda.gov/Food/DietarySupplements/default.htm. Updated April 4, 2016. Accessed Nov. 4, 2018. 2. Hilleman D and Smer A. Manag Care. 2016;25:46-52.
3. Mason RP and Sherratt SCR. Biochem Biophys Res Commun. 2017;483:425-9. 4. Albert BB et al. Sci Rep. 2015;5:7928. 5. Kleiner AC et al. J Sci Food Agric. 2015;95:1260-7. 6. Ritter JC et
al. J Sci Food Agric. 2013:93:1935-9. 7. Jackowski SA et al. J Nutr Sci. 2015;4:e30. 8. Rundblad A et al. Br J Nutr. 2017;117:1291-8. 9. European Medicines Agency, 2018: 712678.
FDA Product Classification1 Food
Clinical Trials/FDA
Pre-Approval1Not Required
Content & Purity2-9
Often difficult to achieve high doses likely needed for efficacy
Often have high saturated fat content
Omega-3 content often overstated
Tend to contain relatively high amounts of
oxidized lipids which may increase CV risk
Can contain PCBs and dioxins at harmful levels
Dietary Supplement Fish Oil:Not Useful for ASCVD Prevention in HTG Patients
Use for Treatment of Disease Not Recommended
Ability to reduce ASCVD Not demonstrated
Purification of Omega-3: O3AEE (Lovaza)
EPA+DHA and Lipid Levels in Patients
with TG >500 mg/dL
*P<0.0001. †P=0.0015. ‡P=0.0059. §P=0.0002 between groups. Pooled analysis (N=82).
Harris WS et al. J Cardiovasc Risk 1997;4:385-91. Pownall HJ et al. Atherosclerosis 1999;143:285-97.
Placebo EPA+DHA (4 g/day)
Baseline
(mg/dL)C
han
ge i
n M
ed
ian
Levels
-60%
-40%
-20%
0%
20%
40%
60%
–4.8*
45.0*
LDL-C
89
–45.0*
6.7*
TG
816
–3.6†
–13.8†
Non-
HDL-C
27
–9.7‡
–1.7‡
TC
296
–42.0*
–0.9*
VLDL-C
175
0.0§
9.1§
HDL-C
22
–4.2‡
–1.9
Statin + EPA/DHA: COMBOS Trial
(TG 200-500 mg/dL)
Me
dia
n C
ha
ng
e f
rom
Ba
se
lin
e (
%)
TG HDL-C
Additional changes to baseline
simvastatin therapy
5
–5
–10
–15
–20
–25
–30
3.4*
–1.2
–6.3
–29.5*
0
–7.2
–27.5*
Apo BNon-
HDL-C
–9.0*
–2.2
*P<0.0001. †P=0.0522. ‡P=0.0232 between groups. COMBOS=Combination of Prescription Omega-3 with Simvastatin.
Davidson MH et al. Clin Ther. 2007;29:1354-67.
Placebo + simvastatin 40 mg/d (n=133)
EPA+DHA 4 g/d + simvastatin 40 mg/d (n=123)
VLDL-C LDL-C
–2.8
0.7†
EVOLVE: DHA+EPA Free Fatty Acid Effects
on Lipid Endpoints, TG >500 mg/dL
*P<0.001. †P<0.01. ‡P<0.05. P-values reflect differences between DHA+EPA free fatty acid (FFA) vs statin+ olive oil.
LSGM=least-squares geometric mean. Kastelein JJP et al. J Clin Lipidol. 2014;8:94-106.
n=99, TG ≥500 but <2000 mg/dL
Baseline
(mg/dL)
-30.9
-9.6
5.8
19.4
3.8
-25.9
-7.6
7.4
19.2
3.8
-40
-30
-20
-10
0
10
20
30
DHA+EPA FFA 4 g/day DHA+EPA FFA 2 g/day
LS
GM
% C
ha
ng
e f
rom
Ba
se
lin
eNon-
HDL-CTG HDL-C Apo BLDL-C
†
*
‡†
†*
ESPRIT: DHA+EPA Free-Fatty-Acid Effects on Lipid
Endpoints, TG 200-500 mg/dL
*P<0.001. †P<0.05. P-values reflect differences between DHA+EPA free fatty acid (FFA) vs statin+ olive oil.
LSGM=least-squares geometric mean. Maki KC et al. Clin Ther 2013;35:1400-11.
n=207, TG ≥200 and <500 mg/dL
Baseline
(mg/dL)
-20.6
-6.9
3.31.3
-2.1
-14.6
-3.9
2.64.6
0.7
-25
-20
-15
-10
-5
0
5
10
†
†
DHA+EPA FFA 4 g/day
DHA+EPA FFA 2 g/day
LS
GM
% C
ha
ng
e f
rom
Ba
se
lin
e
*
*
TG
Non-
HDL-C HDL-C LDL-C Apo B
†
*
Omega-3 CV Outcome Trial Meta-Analysis: No ↓CVD w/ Low-dose EPA+DHA Mix (Diet Sup or Rx)
How Do EPA and DHA Differ?
Omega-3
FA
Molecular
Structures
Adapted from Mozaffarian
D, Wu JH. J Am Coll
Cardiol. 2011;58:2047-67.
Not effective
for ↓TG
Effective
for ↓TG
• Both the amount and
type of omega-3 fatty
acid are important for
TG lowering1
• No head-to-head
studies have been
done to compare the
effects of Prescription
TG-lowering medicine
EPA and DHA Have Different Effects
on LDL-C1-4
TGTG
LOWERING
EPA DHA
NEUTRAL RAISING
LOWERING
LDL-CLDL-C
*Studies were conducted in subjects with varying baseline TG levels.
Arrows are not representative of actual effect on TG or LDL-C; individual effects may vary.
1. Miller M et al. Circulation. 2011;123(20):2292-2333; 2. Jacobson TA et al. J Clin Lipidol. 2012;6(1):5-18;
3. Wei MY, Jacobson TA. Curr Atheroscler Rep. 2011;13(6):474-483; 4. VASCEPA [package insert]. Bedminster, NJ: Amarin
Pharma, Inc; 2017.
20
Purification of Omega-3: Pure EPA (IPE, Vascepa)
EPA: MARINE Trial Lipid Efficacy with
TG >500 mg/dL
*P<0.0001. †P<0.001. ‡P<0.01. §P<0.05. NS = P≥0.05. P-values reflect differences between EPA vs placebo. ITT=intention
to treat; Lp-PLA=Lp-associated phospholipase A; NS=not significant. Bays HE et al. Am J Cardiol. 2011;108:682-90.
ITT PopulationM
ed
ian
Pla
ce
bo
-ad
jus
ted
Ch
an
ge
(%
)
Baseline TG >500 mg/dL
-33.1
-17.7-16.3
-28.6
-3.6-2.3
-8.5
-13.6
-25.8
-35
-30
-25
-20
-15
-10
-5
0
* EPA 4 g/day
Non-
HDL-CTG TC
*
†
VLDL-C HDL-C
NS
LDL-C
NS
Apo B
‡
Lp-
PLA2
†
VLDL-TG
‡
*
-70
-60
-50
-40
-30
-20
-10
0
All Patients No StatinWith Statin
Me
dia
n C
ha
ng
e, %
-65.0
n=19†
-25.8
n=57†-33.1
n=76*
Statin + EPA
TG Lowering
ANCHOR Study: EPA and Lipid Endpoints
(TG 200-500 mg/dL)
*P<0.0001. †P<0.01. P-values reflect differences between EPA vs placebo.
12-week trial in high-risk statin-treated patients (N=702) with residually TG levels (≥200 and <500 mg/dL) despite LDL-C
control (≥40 and <100 mg/dL). ANCHOR=Effect of AMR101 (Ethyl Icosapentate) on Triglyceride (Tg) Levels in Patients on
Statins With High Tg Levels (≥200 and <500 mg/dL). Ballantyne CM et al. Am J Cardiol. 2012;110:984-92.
TG ≥200 and <500 mg/dL
Baseline
(mg/dL)
-21.5
-13.6
-4.5
-6.2
-9.3
-25
-20
-15
-10
-5
0
EPA 4 g/day
Me
dia
n P
lac
eb
o-a
dju
ste
d C
ha
ng
e (
%)
TG
265
*
Non-
HDL-C
128
*
HDL-C
37
†
LDL-C
82
†
Apo B
93
*
-9.9
-16
-19.2
-25.1-30
-20
-10
0
10
Prescription Omega-3 Significantly Reduce
Apo C-III Concentration
EE=ethyl ester; FFA=free fatty acid.
1. Kastelein JJP et al. J Clin Lipidol. 2014;8:94-106. 2. Dunbar RL et al. Lipids Health Dis. 2015;14:98.
3. Ballantyne CM et al. J Clin Lipidol. 2016;Feb 22 [Epub ahead of print].
P value for each trial 0.001 0.001 0.0001 0.0001
compared to its placebo
Note: No head-to-head comparisons are represented or implied.
EPA/DHA FFA 4 g
EVOLVE1 ESPRIT2 ANCHOR3 MARINE3
Baseline TG (mg/dL) ≥500, <2000 ≥200, <500 ≥200, <500 ≥500, ≤2000
Apo C3 concentration change from baseline, vs placebo (%)
EPA EE 4 g
Effects of Rx Omega-3 (EPA) on Remnant Cholesterol:
MARINE and ANCHOR Studies
All patients†
*P<0.05. **P<0.01. †Median differences in percent changes vs placebo are Hodges-Lehmann medians.
EPA=eicosapentaenoic acid ethyl ester; RLP-C=remnant-like particle cholesterol.
Serum RLP-C was measured with an immunoseparation assay by Polymedco (Cortlandt Manor, NY, USA) on the Daytona
chemistry analyzer (Randox, Crumlin, United Kingdom).
Ballantyne CM et al. Presented at the National Lipid Association Scientific Sessions, June 11–14, 2015, Chicago, IL.
Available at: https://www.lipid.org/util/eposters/PDF/172.pdf
MARINE study only
(w & w/o non-randomized statins)†
-29.8-25.8
-40
-30
-20
-10
0
Baseline
mg/dL
MARINE
n=75
45.0
ANCHOR
n=82
13.5
-21.4
-56.8-60
-50
-40
-30
-20
-10
0
Baseline
mg/dL
RL
P-C
Med
ian
ch
an
ge
at
12 w
ks (
vs p
bo
%)
No Statin
n=56
45.0
Statin
n=19
37.0
*** *
*
EPA 4 g/day
RL
P-C
Med
ian
ch
an
ge
at
12 w
ks (
vs p
bo
%)
-2.5
-6.6
-13.6
11.0
-36.0
-2.4
-13.3
-19.0
-1.0
-22.0
-40
-30
-20
-10
0
10
20
MARINE 4 g/day
ANCHOR 4 g/day
Effect of EPA on Inflammatory Markers TG 200-500 and
> 500 mg/dL (12 wks, ITT)
*P<0.01; †P<0.001; ‡P<0.0001 (vs placebo). P values for Lp-PLA2 were adjusted for multiple comparisons.
hsCRP=high-sensitivity C-reactive protein; ICAM-1=intercellular adhesion molecule-1; IL-6=interleukin-6; IPE=icosapent
ethyl; Lp-PLA2=lipoprotein-associated phospholipase A2; NS=not significant; Ox-LDL=oxidized low-density lipoprotein.
Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46.
ICAM-1 Ox-LDL Lp-PLA2 IL-6 hsCRP
Me
dia
n P
lac
eb
o-a
dju
ste
d C
ha
ng
e (
%)
EPA (IPE)
dose
NS NS
NS
‡ †
‡
NS
*
†
NS
MARINE studied 229 patients with very high TG levels ≥500 mg/dL. ANCHOR studied 702 patients with well-controlled LDL-C and residually high TG levels 200–500 mg/dL.
Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46.
EPA Treatment Lowers Levels of Inflammatory and Oxidative Markers
-27.4
-67.9
-2.7
-33.2
-80
-60
-40
-20
0
No Statin With Statin
Median placebo-adjusted change (%)
4 g/day
2 g/day
Additive hsCRP reduction with IPE + Statin
MARINE + ANCHOR Pooled (N=931)
hsCRP decrease with EPA is enhanced with intensive statin use
-13.6
-36
-6.6
-19.0
-22.0
-13.3
-40
-35
-30
-25
-20
-15
-10
-5
0
Me
dia
n C
han
ge
fro
m B
as
eli
ne
vs
Pla
ce
bo
(%
)
Me
dia
n C
han
ge
fro
m B
as
eli
ne
vs
Pla
ce
bo
(%
)
MARINE, icosapent ethyl 4 g/day
ANCHOR, icosapent ethyl 4 g/day
Markers of Inflammation
Lp-PLA2 hsCRP Ox-LDL
EPA (4 g)
Statins
Lipid Therapy
EPA/DHA (4 g)
hsCRP Levels
EPA (4 g) + Statin
Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46. Dunbar RL et al. Lipids Health Dis. 2015:14:98. Ridker PM et al. N Engl J Med. 2008;359:2195-207.
Bohula EA et al. Circulation. 2015;132:1224-33. Pradhan AD et al. Circulation. 2018;138:141-9.
Ezetimibe
Ezetimibe + Statin
Variability Among Lipid Therapies In hsCRP Effect
PCSK9i + Statin
EPA vs DHA Anti-inflammatory Effects
• Both are metabolized to:
– Anti-inflammatory cytokines
– Inflammation-resolving factors
– Fibrosis-resolving factors
• EPA alone
– Same length as arachidonic-acid (AA), so
– Blocks production of pro-inflammatory cytokines
from AA
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
EPA vs Other TG-lowering Agents Effects on Oxidation of Membrane Lipid Hyperglycemia
In Vitro Model
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
96 hours; **P<0.001 vs vehicle-treated control. ‡P<0.001 vs glucose-treated control. §§P<0.001 vs EPA. ¶P<0.001 vs oxEPA1
(Student-Newman-Keuls multiple comparisons test; overall ANOVA: P<0.0001, F=278.23). Values are mean ± SD (N = 6).
These findings have been noted by R. Preston Mason, PhD (unpublished data, 2015).
EPA vs EA & ETE: Unique Structure of EPA Has Antioxidant Activity vs Glucose-induced Membrane Lipid Peroxidation
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Adapted from Mason RP and Jacob RF. Biochim Biophys Acta. 2015;1848:502-509.
Schematic Illustration of the Distinct Membrane Structural & Biochemical Effects of EPA vs Other TG-lowering Agents
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Schematic Illustration of the Protective Effects of EPA on sdLDL Lipid Oxidation
Adapted from: Mason RP, Jacob RF. Diabetes. 2015;64,Suppl 1:A178-A179.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
EPA Uniquely
Inhibits Lipoprotein
Oxidation:
The antioxidant properties of
EPA were not observed with
other TG-lowering agents.
Each agent was tested at 10 µM
Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Effects of a DS Omega-3 (Fatty Acid Extract) vs Non-Oxidized and Partially Oxidized Preparations of EPA + DHA on Human sdLDL Oxidation
Vehicle
MD
A E
qu
ivale
nts
(μ
M)
DS
12
0
10
8
6
4
2
§
*
§†*
† *
EPA
+
DHA
oxEPA
+
oxDHA
*P<0.001 vs vehicle alone. †P<0.001 vs DS. §P<0.001 vs oxEPA + oxDHA (Student-Newman-Keuls
multiple comparisons test; overall ANOVA: P<0.0001, F=993.26). Values are mean ± SD (N=3).
Mason RP, Sherratt SCR. Biochem Biophys Res Commun. 2016;1-5.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
EPA Uniquely
Maintains
Inhibition of
Lipoprotein
Oxidation:
The antioxidant properties of
EPA were sustained over time,
while those of DHA were lost.
Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Peroxide, Anisidine, and TOTOX Values Measured in Rx and Leading Dietary Supplements
Mason RP, Sherratt SCR. Biochem Biophys Res Commun. 2016;1-5.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
EPA and Atorvastatin Metabolite Inhibited sdLDL Oxidation to a Greater Extent
• EPA and ATM
independently inhibit
oxidation of apoB-
containing lipoproteins
• EPA and ATM effects are at
a minimum additive and
may approach synergy in
LDL and sdLDL
Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
EPA Uniquely
Maintains
Inhibition of
Lipoprotein
Oxidation:
The antioxidant properties of
EPA were sustained over time,
while those of DHA were lost.
Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Effects of EPA and/or Statin on
Endothelial Function
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Nitric Oxide Is a Key Mediator of Renal/Vascular Protection
Vessel lumen
Vascular smooth muscle cells
NO
GUANYLATE
CYCLASE
GTP cGMP
NO
NO Platelet
inhibition
Relaxation
Cell growth/proliferation
Matrix formation
Leukocyte migration
Subendothelium
Behrendt and Ganz. Am J Cardiol. 2002;90(suppl):40L.
Vita. J Card Fail. 2003;9(suppl nitric oxide):S199.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
+ + +EPA Atorv EPA
+Atorv
***
*
***
†
§
Vehicle oxLDL oxLDL oxLDL oxLDL0.0
0.5
1.0
1.5
2.0
2.5
NO
/ON
OO
– R
ele
ase
Ra
tio
Atorvastatin active metabolite was used in this study. Values are mean ± SD (N=3-6). *P<0.05 and ***P<0.001 vs ox LDL. †P<0.01 vs
ox LDL + EPA. §P<0.001 vs ox LDL + Atorv (Student-Newman-Keuls multiple comparison test; overall ANOVA: P<0.0001, F=25.827).
Mason RP et al. J Clin Lipidol. 2014;8:342-343.
Combined Effects of EPA and Atorvastatin on Human Endothelial Function in vitro after Treatment with Oxidized LDL
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Exposed to 300 mg/dL Glucose
**P<0.001 versus Control; *P<0.01 versus Control; †P<0.001 versus vehicle; §P<0.05 versus EPA + ATM.
(Student-Newman-Keuls multiple comparisons test; overall ANOVA: P<0.0001, F=38.885). Values are mean ± SEM (N = 4-8)
Mason RP et al. J Am Coll Cardiol. 2016 (in press).
Effects of EPA and ATM on NO Released from Glomerular Endothelial Cells Under Hyperglycemic Conditions ex vivo
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
OM=omega.
Mason RP et al. J Clin Lipidol. 2014;8:342-343.
Potential Co-protective Effects of EPA & Atorvastatin on Human EC Function
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
EPA vs DHA Other Long-Chain
Fatty Acids and Other TG-Lowering Agents
on Membrane Fluidity,
and Cholesterol Domain Formation
in Model Membranes
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Cholesterol Crystals Can Evolve from Excess Cholesterol Domain Formation and Associate w/ Cell Death Atherosclerosis and Plaque Rupture
Kellner-Weibel G, Mason RP, et al. Arterioscler Thromb Vasc Biol. 1999;19:1891-1898.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Dose-dependent effects of EPA and DHA on the apparent rotational correlation time (ARCT)
measured for diphenylhexatriene (DPH) in POPC membranes prepared at 50 mol% cholesterol
DHA Increases Membrane Fluidity Compared to EPA
Mason RP et al. Biochim Biophys Acta. 2016;1858:3131-3140.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Schematic Illustration of the Distinct Membrane Structural & Lipid Dynamic Effects of EPA vs DHA
Mason RP et al. Biochim Biophys Acta. 2016;1858:3131-3140.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Oxidative Damage to Membrane Lipids Leads to Cholesterol Crystalline Domains and Cell Injury
Adapted from: Mason RP, Jacob RF. Adv Exp Med Biol. 2015;842:231-245.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
Cholesterol Domain-Reducing Effects of EPA Not Reproduced by Other Fatty Acids or TG-Lowering Agents
Mason RP et al. Biochim Biophys Acta. 2016;1858:3131-3140.
Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.
In vitro Effects of EPA: Overall Summary
• EPA inhibits changes in membrane organization
through a potent antioxidant mechanism1
• EPA has unique antioxidant benefits in
apoB-containing compared to other TG-lowering
agents and DHA2
• EPA may reduce CV risk through these novel effects
on cell membranes3
• EPA may reduce inflammation and improve
endothelial function due to its unique structure3
1. Mason RP et al. Biochim Biophys Acta. 2015;1848:502-509. 2. Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40. 3.
Mason RP et al. Biochim Biophys Acta. 2016;1858:3131-3140.
Pros of EPA 1. Fits between PL legs (in lipoproteins & cells):• More stable in PL
mono/bilayer• Longer/better antiox. effect• No ↑chol crystals (vs ↑w/
DHA)2. Fits in AA-series enzymes:• ↓AA→pro-inflam cytok.• ↓hsCRP3. No inhibition of LDL-R → modest ↓LDL-C/apoBPros of DHA 1. Coils up between PL legs so↑Membr. fluidity (good vs bad?)2. Modest ↑HDL-C (vs ↓w/ EPA)
How May EPA and DHA DifferRe: Anti-Atherosclerotic Mechanisms?
Bottom Line:• EPA appears
better than DHA in vitro + in vivo, but this is not yet proven; more research needed!
EPA and DHA Appear to be Similar Re:• ↓TG• ↓LpPLA2
• Anti-platelet• Anti/pro-
arrhythmia
IPE vs O3AEE vs O3 Dietary Supplements
Yes (4%) Yes (16%)
EPA Reduces Plaque Volume Evaluated by
Backscatter Intravascular Ultrasound (IB-IVUS)
Wilcoxon signed-rank test. Ando K on behalf of the CHERRY Investigators at the AHA Scientific Sessions, November 8, 2015.
0
100
200
Baseline Follow up
0
100
200
Baseline Follow up
Pitavastatin group Pitavastatin / EPA group
72.7(43.9, 121.2) 67.4
(43.4, 117.2)
74.5(45.6, 107.3)
61.4(40.3, 91.4)
P=0.108 P<0.001
241 patients who received primary percutaneous coronary intervention (PCI) using IB-
IVUS in 6 hospitals were randomized to pitavastatin 4 mg/day or pitavastatin 4 mg/day +
EPA 1800 mg/day and followed for 6–8 months
mm
3
mm
3
JELIS: EPA Reduced Major Adverse Coronary Events (MACE)*
in Hypercholesterolemic Patients on Statins
Yokoyama M et al. Lancet. 2007;369:1090-8.
No. at Risk
Control
EPA
0 1 4 5 Years
9319 8931 8671 8433 8192 7958
9326 8929 8658 8389 8153 7924
Cu
mu
lati
ve I
ncid
en
ce o
f M
ajo
r
Co
ron
ary
Even
ts
(%)
4
P=0.011
Statin + EPA 1.8g/day
Statin only3
2
1
0
HR (95% CI): 0.81 (0.69–0.95)
↓
2 3
N=18,645 Japanese pts with TC ≥251 mg/dL prior to baseline statin Rx. Baseline TG=153 mg/dL.
Statin up-titrated to 20 mg pravastatin or 10 mg simvastatin for LDL-C control.
*Primary endpoint: sudden cardiac death, fatal and non-fatal MI, unstable angina pectoris,
angioplasty, stenting, or coronary artery bypass graft.
RRR
–19%
*Pre-specified analysis in primary prevention subjects. MACE=major adverse CV event.
Saito Y et al. Atherosclerosis. 2008;200:135-40.
JELIS: Larger Decrease in MACE in Subjects with
TG >150 mg/dL & HDL-C <40 mg/dL*
HR and P-value
adjusted for age,
gender, smoking,
diabetes, and HTN
No. of patients
Control 475 444 432 414 400 392
EPA 482 455 443 427 413 403
0 1 2 3 4 5 Years
Cu
mu
lati
ve i
ncid
en
ce o
f m
ajo
r
co
ron
ary
even
ts (
%)
EPA 1.8 gm/day group
Control group
RRR
–53%
HR: 0.47
95% CI: 0.23–0.98
P=0.043
5.0
4.0
3.0
2.0
1.0
0
Omega-3 CV Outcome Trial Meta-Analysis:
No ↓CVD w/ Low-dose EPA+DHA Mix; ↓CVD w/ Mid-dose Pure EPA
REDUCE-IT Design
1. Age ≥45 y with established CVD (2o Prevention)
or high risk 1o prevention: ≥50 y with diabetes +
≥1 additional CVD risk factor
2. Fasting TG levels 135-500 mg/dL
3. LDL-C 40-100 mg/dL and on stable statin Rx (±
ezetimibe) for ≥4 weeks prior to qualifying
measurements for randomization
Primary Endpoint Events: CV death, nonfatal MI, nonfatal stroke, coronary revasc, hospitalization for unstable angina
Key Secondary Endpoint Events: CV death, nonfatal MI, nonfatal stroke
Double-blind study; Events adjudicated by CEC that was blinded to treatment during adjudication
Screened
N=19,212
Randomized
N=8179
(43% of screened)
Icosapent Ethyl
4 grams/day
N=4089
Placebo
N=4090
Known vital status 4083 (99.9%) Known vital status 4077 (99.7%)
Median trial
follow up
4.9 yr
Bhatt, DL, Steg PG, Brinton, EA. Clinical Cardiology. 2017;40:138–148 and Bhatt DL, Steg PG, Miller M, et al. NEJM. 2019; 380:11-22.
REDUCE-IT Design
1. Age ≥45 y with established CVD (2o Prevention)
or high risk 1o prevention: ≥50 y with diabetes +
≥1 additional CVD risk factor
2. Fasting TG levels 135-500 mg/dL
3. LDL-C 40-100 mg/dL and on stable statin Rx (±
ezetimibe) for ≥4 weeks prior to qualifying
measurements for randomization
Primary Endpoint Events: CV death, nonfatal MI, nonfatal stroke, coronary revasc, hospitalization for unstable angina
Key Secondary Endpoint Events: CV death, nonfatal MI, nonfatal stroke
Double-blind study; Events adjudicated by CEC that was blinded to treatment during adjudication
Screened
N=19,212
Randomized
N=8179
(43% of screened)
Icosapent Ethyl
4 grams/day
N=4089
Placebo
N=4090
Known vital status 4083 (99.9%) Known vital status 4077 (99.7%)
Median trial
follow up
4.9 yr
Bhatt, DL, Steg PG, Brinton, EA. Clinical Cardiology. 2017;40:138–148 and Bhatt DL, Steg PG, Miller M, et al. NEJM. 2019; 380:11-22.
↑↑ASCVD risk despite LDL-C controlled on statin & TG >135
Key Baseline Characteristics
Icosapent Ethyl
(N=4089)
Placebo
(N=4090)
Age (years) 64 64
Female, % 28.4% 29.2%
CV Risk Category, %
Secondary Prevention Cohort 70.7% 70.7%
Primary Prevention Cohort 29.3% 29.3%
Prior Atherosclerotic Cardiovascular Disease, % 68.9% 69.3%
Prior Atherosclerotic Cerebrovascular Disease, % 15.7% 16.2%
Prior Atherosclerotic Peripheral Artery Disease, % 9.5% 9.5%
LDL-C (mg/dL), Median (Q1-Q3) 74.0 (61.5 - 88.0) 76.0 (63.0 - 89.0)
Triglycerides (mg/dL), Median (Q1-Q3) 216.5 (176.5 - 272.0) 216.0 (175.5 - 274.0)
Triglyceride Category (by Tertiles)*
≥81 to ≤190 mg/dL 1378 (33.7%) 1381 (33.8%)
>190 to ≤250 mg/dL 1370 (33.5%) 1326 (32.4%)
>250 to ≤1401 mg/dL 1338 (32.7%) 1382 (33.8%)
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019. Bhatt DL. ACC 2019, New Orleans.
*Baseline TG calculated as average of final screening TG and subsequent TG value from date of randomization.
Key Background Medical Therapy
Icosapent Ethyl
(N=4089)
Placebo
(N=4090)
Antiplatelet 3257 (79.7%) 3236 (79.1%)
One Antiplatelet agent 2416 (59.1%) 2408 (58.9%)
> 2 Antiplatelets 841 (20.6%) 828 (20.2%)
Anticoagulant 385 (9.4%) 390 (9.5%)
ACEi or ARB 3164 (77.4%) 3176 (77.7%)
Beta Blocker 2902 (71.0%) 2880 (70.4%)
Statin 4077 (99.7%) 4068 (99.5%)
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
Primary End Point:CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Icosapent Ethyl
23.0%Placebo
28.3%
Years since Randomization
Pa
tie
nts
wit
h a
n E
ve
nt
(%)
0 1 2 3 4 5
0
10
20
30
P=0.00000001
RRR = 24.8%
ARR = 4.8%
NNT = 21 (95% CI, 15–33)
Hazard Ratio, 0.75(95% CI, 0.68–0.83)
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL. AHA 2018, Chicago.
20.0%
16.2%
Icosapent Ethyl
Placebo
Key Secondary End Point:CV Death, MI, Stroke
Hazard Ratio, 0.74(95% CI, 0.65–0.83)
RRR = 26.5%
ARR = 3.6%
NNT = 28 (95% CI, 20–47)
P=0.0000006
Years since Randomization
Pa
tie
nts
wit
h a
n E
ve
nt
(%)
0 1 2 3 4 5
0
10
20
30
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL. AHA 2018, Chicago.
Omega-3 CV Outcome Trials:
No ↓CVD w/ Low-dose EPA+DHA Mix; Yes ↓CVD w/ Mid-dose Pure EPA
REDUCE-IT is 2nd of 2 CVOT’s w/ ↓CVD from EPA as Statin AdjunctTWO Best RRRs of All: JELIS ↓19% and REDUCE-IT ↓25%
Total Mortality 0.87 (0.74–1.02) 0.09
Endpoint
Primary Composite (ITT)
Key Secondary Composite (ITT)
Cardiovascular Death orNonfatal Myocardial Infarction
Fatal or Nonfatal Myocardial Infarction
Urgent or Emergent Revascularization
Cardiovascular Death
Hospitalization for Unstable Angina
Fatal or Nonfatal Stroke
Total Mortality, Nonfatal MyocardialInfarction, or Nonfatal Stroke
310/4090 (7.6%)
Placebo
n/N (%)
901/4090 (22.0%)
606/4090 (14.8%)
507/4090 (12.4%)
355/4090 (8.7%)
321/4090 (7.8%)
213/4090 (5.2%)
157/4090 (3.8%)
134/4090 (3.3%)
690/4090 (16.9%)
274/4089 (6.7%)
Icosapent Ethyl
n/N (%)
705/4089 (17.2%)
459/4089 (11.2%)
392/4089 (9.6%)
250/4089 (6.1%)
216/4089 (5.3%)
174/4089 (4.3%)
108/4089 (2.6%)
98/4089 (2.4%)
549/4089 (13.4%)
Hazard Ratio (95% CI)
0.75 (0.68–0.83)
0.74 (0.65–0.83)
0.75 (0.66–0.86)
0.69 (0.58–0.81)
0.65 (0.55–0.78)
0.80 (0.66–0.98)
0.68 (0.53–0.87)
0.72 (0.55–0.93)
0.77 (0.69–0.86)
P-value
<0.001
<0.001
<0.001
<0.001
<0.001
0.03
0.002
0.01
<0.001
Hazard Ratio
(95% CI)
1.4
Icosapent Ethyl Better Placebo Better
0.4 1.0
Prespecified Hierarchical TestingRRR
23%
28%
32%
20%
35%
31%
25%
26%
25%
13%
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL. AHA 2018, Chicago.
REDUCE-IT appendix. Bhatt, DL. NEJM epub Nov 10, 2018
REDUCE-IT: Individual Elements of Primary Endpoint (5-POINT MACE)
143
126
1,546
901
376
Placebo
[N=4090]
Nu
mb
er
of
Pri
mary
Co
mp
os
ite
En
dp
oin
tE
ve
nts
3rd1st 2nd ≥4
1,076
Icosapent Ethyl
[N=4089]
7263
705
2362nd EventsHR 0.68
(95% CI, 0.60-0.78)
1st EventsHR 0.75
(95% CI, 0.68-0.83) P=0.000000016
≥4 EventsRR 0.52
(95% CI, 0.38-0.70)
3rd EventsHR 0.69
(95% CI, 0.59-0.82)
RR 0.70(95% CI, 0.62-0.78)
P=0.00000000036
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
Reduced Dataset Event No.
-63
-71
-196
-140
-470
No. ofFewerCases
30% Reduction in Total Events
First and Subsequent Events
Note: WLW method for the 1st events, 2nd events, and 3rd events categories;
Negative binomial model for ≥4th events and overall treatment comparison.
1,600
1,200
800
400
0
600
1,000
1,400
200
Total (First and Subsequent) EventsPrimary: CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
Primary Composite Endpoint
0 1
Years since Randomization
5
Cu
mm
ula
tive E
ven
ts p
er
Pati
en
t
2 3 40.0
0.1
0.2
0.3
0.4
0.6
0.5
Placebo: Total Events
Icosapent Ethyl: Total Events
Placebo: First Events
Icosapent Ethyl: First Events
HR, 0.75
(95% CI, 0.68–0.83)
P=0.00000001
RR, 0.70(95% CI, 0.62–0.78)
P=0.00000000036
Primary
Composite
Endpoint
-159
Cardiovascular
Death
-12
Fatal or
Nonfatal MI
-42 Fatal or
Nonfatal
Stroke
-14
Coronary
Revascularization
-76
Hospitalization
for Unstable
Angina
-16
-100
-150
-200
-50
0
Ris
k D
iffe
ren
ce
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
For Every 1000 Patients Treated with Icosapent Ethyl for 5 Years:
.
PowerPoint Presentation
Rx EPA (IPE) ↓ASCVD in patients with
baseline TG 135-200 ≈ TG 200-500!
#AHA18: Cholesterol Guidelines full update; omega-3s and CV
events; yoga and risk reduction - Message (HTML)
Rx EPA (IPE) ↓ASCVD in patients with
baseline TG 135-150 ≈ TG 150-500!!
TOTAL EVENTS – Primary Composite Endpoint/Subgroup Icosapent Ethyl Placebo RR (95% CI) P-value
Rate per 1000
Patient Years
Rate per 1000
Patient Years
Primary Composite Endpoint (ITT) 61.1 88.8 0.70 (0.62–0.78) <0.0001
Baseline Triglycerides by Tertiles*
≥81 to ≤190 mg/dL 56.4 74.5 0.74 (0.61–0.90) 0.0025
>190 to ≤250 mg/dL 63.2 86.8 0.77 (0.63–0.95) 0.0120
>250 to ≤1401 mg/dL 64.4 107.4 0.60 (0.50–0.73) <0.0001
Primary Composite Endpoint:Total Endpoint Events by Baseline TG Tertiles
Bhatt DL. ACC 2019, New Orleans.
Placebo
Better
Icosapent Ethyl
Better
1.00.2 1.40.6 1.8 *P (interaction) = 0.17
↓CVD w/ EPA Was
Comparable w/ On-Rx TG
> vs < 150 mg/dL
Similar results were seen with the key secondary endpoint
Bhatt DL, et al. N Engl J Med. 2019;380(1):11-22.
Did ASCVD↓ More in Subgroup with TG > 200 PLUS HDL-C < 35? Maybe NOT
Subgroup % Subjects w/ CVD Events P-heterogeneity
TG ≥200 mg/dL and HDL-C ≤35 mg/dL
Icosapent Ethyl
Placebo HR (95% CI)0.04
Yes 18.1 27.0 0.62 (0.51-0.77)
No 17.0 20.9 0.79 (0.71-0.88)
Above data are with 1o endpoint, 5-point MACE, but
P-value only 0.50 (NS) for stronger 2o endpoint (“Hard” 3-point MACE)
REDUCE-IT Surprise:
In Mild-Moderate HTG Patients
Baseline & On-Rx TG Levels Don’t Seem to Matter!!
(opposite of LDL-C)
PowerPoint Presentation
(No Difference in Overall TEAE)
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
EPA Effects on Arrhythmias and Their SequelaeIPE 4g/d Pbo HR (95%CI) P value
Atrial* % N % N
Total Atr. Fibrillation 5.3 215 3.9 159 Sig↑** 0.003
Hosp. for Atr. Fib. 3.1 127 2.1 86 Sig↑** 0.004
Ventricular(?)
Sudden Cardiac Death 1.5 61 2.1 87 .69 (.50-.96) Sig↓**
Cardiac Arrest 0.5 22 1.0 42 .52 (.31-.86) Sig↓**
Total
Arrhyth. Req. Hosp. >24h 4.6 188 3.8 154 1.21 (.97-1.49) NS
*No increases in the worst AFib sequelae: TIA, CHF, dyspnea or fatigue. **Not given.
JELIS provided no information about arrhythmias. See Yokoyama M Lancet 2007;369;1090-98.
EPA+DHA trials/studies sugg: ↑atrial fibrillation (↓if post cardiac surg) vs ↓ventricular events. (see Kowey, PR. JAMA;2010;304:2363-72; Mozaffarian, D. JACC;2011;58:2047-67; von Schacky, C. Frontiers in
Physiol. 2012; 3; 88. Christou, GA. Int J Mol Sci 2015;16: 22870-87 Siscovick, DS. Circul. 2017;135;e867-84.)
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPointTrend Towards ↑Total Serious Bleeding Events—Likely Real
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPointNo Apparent ↑Intracranial or Fatal Bleeding Events
Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint
JELIS reported modestly ↑total bleeding events: 1.1% vs 0.6% p=0.006 (no ↑intracranial bleeding; 1.8 g/d IPE on high-fish diet)
EPA Safety and Tolerability in Long-Term CVOT (JELIS, N=18,645)
CPK=creatine phosphokinase; GOT=glutamic oxaloacetic transaminase *No between-group differences in stroke (incl cerebral or subarachnoid hemorrhage). Hazard ratio for hemorrhagic stroke 1.12 (0.91–1.39, P=0.272).• The rate of discontinuation due to treatment-related adverse effects was 11.7% in the EPA + statin group and 7.2% in the statin only group• Most adverse events attributed to EPA treatment were regarded as mild by the investigators
EPA Group Control P Value
Pain (joint, lumbar, muscle) 1.6% 2.0% 0.04
Gastrointestinal disturbance (nausea, diarrhea, epigastric
discomfort)3.8% 1.7% <0.0001
Skin abnormality (eruption, itching, exanthema, eczema) 1.7% 0.7% <0.0001
Hemorrhage (cerebral, fundal, epistaxis, subcutaneous)* 1.1% 0.6% 0.0006
Abnormal laboratory data
•Total
•CPK increased
•GOT increased
•Blood sugar level increased
4.1%
1.4%
0.6%
0.4%
3.5%
1.2%
0.4%
0.3%
0.03
0.52
0.03
0.17
Yokoyama M et al. Lancet. 2007;369(9567):1090-1098.
90
Plasma EPA w/ Epadel 1.8 g/d in Japanese
vs Vascepa 4 g/d in Non-Japanese
Institute for Clinical and Economic Review, 2019. Draft Evidence Report. Additive Therapies for Cardiovascular Disease: Effectiveness and Value. https://icer-review.org.
IPE is Very Cost-Effective: REDUCE-IT Data
A preliminary report from the Institute for Clinical and Economic Review (ICER) on the effectiveness and value of icosapent ethyl• Comparative Clinical Effectiveness
“For adults with established CVD or at high risk of cardiovascular events who are being treated with statins, we have high certainty that icosapent ethyl provides a small-to-substantial net health benefit (“B+”).
• Long-term Cost Effectiveness
Icosapent ethyl (in patients receiving statins) provides clinical benefit in terms of gains in quality-adjusted survival compared to optimal medical management alone in the adult with established CVD cohort and without known CVD but at high risk for CVD events.
This translated into incremental cost-effectiveness estimates that fell below commonly cited cost-effectiveness thresholds under the assumptions used for this analysis, which were willingness-to-pay thresholds of both $50,000 per QALY and $100,000 per QALY gained.
Icosapent ethyl vs. optimal medical management yields $18,000 per QALY gained at the current
wholesale acquisition cost of $303.65 per month.
CVD Outcome Trials of Full-Dose Prescription Omega-3:
Pure EPA vs EPA + DHA Mix
1. Bhatt, DL, NEJM. 2019; 380:11-22. 2. http://www.clinicaltrials.gov.
REDUCE-IT1
(Results November ‘18)STRENGTH2
(Ongoing—Results 2020?)
Omega-3 type
DoseEPA (O3AEE)
4 g/day
EPA+DHA (FFA)
4 g/day
Population International International
Subjects/ CVD events 8179/1612 Estimated 13,000/~1600
GenderMen and non-pregnant or sterile women
ages 45 or olderMen or women, ≥18 years of age
Risk ProfilePrior ASCVD (70%),
High CV risk (30%); DM ~50%
Prior ASCVD (50%),
High CV risk (50%)
Follow-up 4.9 years ~3 years (planned)
Statin Use100%
(LDL-C <100l)
100%
(LDL-C <100 or max tol statin dose)
Primary End PointExpanded Major adverse
cardiac event (5-point)
Expanded Major adverse
cardiac event (5-point)
Statistical PowerPowered for 15% RRR
25% RRR Seen Powered for 15% RRR
Baseline TG/HDL-C 135-500 mg/dL/HDL is NA 180-500/<42 men & <47 women
Rx EPA O3AEE (25% RRR, ~$220/mo) vs DHA-Containing Alternatives:
• Rx EPA+DHA O3AEE (generic Lovaza) ~$40/mo, but– ↓CVD not proven yet (likely not ever?)– +DHA net differences might be adverse, but– OK if pt can’t afford Rx EPA?? (=payer won’t pay) if DHA ≈ EPA
(i.e. if STRENGTH ≈ REDUCE-IT)• Rx EPA+DHA FFA
– DHA net effects vs EPA: might have less ↓CVD (?)– ↑GI absorption benefit is small and assoc w/ ↑GI side effects– (Not yet clinically available)– May be shown ≈ pure EPA for ↓CVD (if STRENGTH ≈
REDUCE-IT), but if so, might default Rx be generic Lovaza?– Likely $$ similar to branded IPE (but low-dose would be ½ cost)– Advantages vs IPE: qd dosing, low dose ok (linear dose-resp.)?
In Vivo Human Trial ASCVD Results:
Pure EPA vs EPA + DHA Mix
Evidence Type Pure EPA EPA+DHA Mix
Coronary Athero
Trials
Beneficial No data
CVOT Results Beneficial:REDUCE-IT & JELIS
Low-dose Negative(STRENGTH ongoing)
Summary Beneficial As beneficial vs less??
Fibrates as “TG-Lowering for ASCVD Prevention”
Adjuncts to Statin Mono-Rx• Gemfibrozil—good mono-Rx CVD data but not practical
as statin adjunct• Fenofibrate—cheap, safe, good ↓TG but CVD data w/
statin not convincing (and confusing re: formulations)• Pemafibrate—not yet available but may be shown to
↓ASCVD in PROMINENT (results ~2022)
Bottom line: Evidence lacking for generic TG-loweringw/ fibrate (or niacin)—use only EPA (=IPE) for now
Conclusion: ↓ASCVD (etc.) in Mild-Moderate HTG (fasting TG 135-200)
• Rx EPA—best statin adjunct if TG >135 (& payer ok)• Rx EPA+DHA (generic Lovaza)??—if TG >135 & pt can’t
afford EPA, and if STRENGTH ≈ REDUCE-IT• Rx EPA+DHA FFA—not available yet, if STRENGTH
≈REDUCE-IT→O3AEE mix? (generic Lovaza vs. Epanova)• Fibrates: feno vs pemafib.? Not yet, wait for PROMINENT• Further LDL-C Lowering beyond statins if LDL-C > thresh.
– Ezetimibe (~$9/mo), if LDL-C ~70-130 and pill-count ok
– PCSK9i if LDL-C >100 and cost ok (~$450/mo)
• SGLT2i: if CHF, BP, CKD (ESRD) & A1c >~8 (payer ok?)
• GLP1-RA: if ↓Obesity, CKD, A1c >~8 (payer ok?)
1
2
3