gregory pokrywka md facp fnla faspc ncmp...wvafp clinical lipidology update 2020: new life for...

WVAFP Clinical Lipidology Update 2020 New life

for Vascular EPA Updated Clinical Guidelines and

Vascular Imaging for Non-Cardiologists

Gregory Pokrywka MD FACP FNLA FASPC NCMP Asst Professor of Medicine Johns Hopkins University

Diplomate of the American Board of Clinical Lipidology

Fellow of the American College of Physicians National Lipid

Association and American Society for Preventive Cardiology

North American Menopause Society Certified Menopause

Practitioner

Director Baltimore Lipid Center

httpwwwbaltimorelipidcentercom

gpokmdverizonnet

Twitter gpokmd

wwwlipidorg

httpswwwaspconlineorg

wwwlearnyourlipidscom

Virginia Council of Nurse Practitioners

Presentation Title

VCNP Clinical Lipidology Update 2020 New life for Vascular EPA

Updated Clinical Guidelines and Vascular Imaging for Non-Cardiologists

I will not discuss off-label medication uses or investigational use in my presentation

I have financial relationships to disclose

Employer Self

Consultant Esperion

Stockholder

Research Support

Honorarium Speakerrsquos Bureau for Amarin Amgen Sanofi Regeneron

ldquoI have some bad news

While your cholesterol level has remained the same

the guidelines have changedrdquo

We Are in a New Era of Lipid

Management

Prevention of CVD ndash We Should Start Earlier

This analysis of NHANES data demonstrates that CVD is not only a disease that affects older individuals On the contrary virtually half the total events in men and almost one-third in women occur before age 65 years

For those with premature CVD events their personal family and societal contributions are cut short or diminished earlier their earnings losses are greater and for those who survive their period of care is longer

Preventive therapy in current lipid guidelines is triggered primarily by risk exceeding a defined threshold Because risk is strongly associated with age the indication for preventive therapy increases substantially after age 60 years from about 30 to almost 80

Sniderman Thanassoulis et al JAMA Cardiology E1-E2 Published online May 18 2016


These results demonstrate that by age 60 many CVD events have already occurred

Furthermore by age 60 years asymptomatic intramural atherosclerotic disease is well advanced in many other individuals

These findings highlight the need to refine strategies to identify individuals younger than 60 years who are candidates for preventive therapies


FIND A WAY TO MONITOR ATHEROGENIC LIPOPROTEIN NUMBERS THAT WORKS FOR YOU (More particles = more plaque = more clinical events REGARDLESS OF THE CHOLESTEROL

CONCENTRATION )

A) NonHDLC = (TC ndash HDLC) (optimum = lt 130 mgdl Hi risk pts lt 100 mgdl V Hi risk pts )

B) apoB (optimum = lt 80 mgdl Hi risk pts lt 60 mgdl V Hi risk pts

C) LDL-P by NMR (optimum = lt 1000 nmoll Hi risk pts lt750 nmolL V Hi risk pts )

The ABCs of

Primary

Cardiovascular

Prevention 2019

Update

Mar 21

2019 | Abdulha

mied Alfaddagh

MD Kelly Arps

MD Roger S

Blumenthal MD

FACC Seth Shay

Martin MD MHS

FACC

httpswwwaccor

glatest-in-

cardiologyarticles

201903211439

abcs-of-primary-

cv-prevention-

2019-update-gl-

prevention

Nutrition Lifestyle Recommendations Lipids and BP

bullDietary patterns emphasis-based

ndash DASH and Mediterranean-style

eating plans

bullFruits vegetables and whole grains

bull30 ndash 35 fat intake

ndash lt6 saturated fats no trans fats

bullLow sodium (lt2400 mgday)

bullCut out processed or pre-prepared food

bullHealthy eating for a lifetime

Eckel RH et al Circulation 129 (25 Suppl 2)S76-99 2014

Best evidence to reduce MI risk is the Mediterranean diet

Physical Activity Guidelines for Lipids amp Insulin Resistance Reduction

Advise adults to engage in physical activity bull Aerobic activity 3 to 4 sessions a week

bull lasting on average 45-60 min per session

bull involving moderate-to-vigorous intensity physical activity

bull Resistance training at least twice week (eg Harvard Health newsletter)

bull Time-Restricted Feeding (TRF eg 6-10 hour feeding window) for insulin resistant (and for ALL patients interested in prolonging ldquohealth-spanrdquo- See ldquoLifespanrdquo by David Sinclair PhD)

bull BETTER SLEEP 7-8 hours ldquoWhy We Sleeprdquo by Dr Matthew Walker Cognitive Behavioral Training (CBT) apps from httpswwwsleepfoundationorg


Best evidence is brisk walking 30 min a day 5 days a week

ACC Risk Calculator Plus to Assess Risk Category

1 For primary prevention use the calculator to Assess Risk Category

ge75 to lt20

ldquoIntermediate Riskrdquo

ge20

ldquoHigh Riskrdquo

lt5

ldquoLow Riskrdquo

5 to lt75

ldquoBorderline Riskrdquo

2 Then use the new ACCAHA Blood Cholesterol guideline algorithms to guide

management

bull Estimates 10-year hard ASCVD (nonfatal MI CHD death stroke) for ages 40-79 and lifetime risk for ages 20-59

bull Intended to promote patient-provider risk discussion and best strategies to reduce risk

bull ge75 identifies statin eligibility not a mandatory prescription for a statin

ACC=American College of Cardiology AHA=American Heart Assciation ASCVD=atherosclerotic cardiovascular disease

toolsaccorgascvd-risk-estimator-pluscalculateestimate

Assessment of ASCVD Risk Enhancing Factors

2019 ACCAHA Primary Prevention Guideline

Courtesy of Erin Michos

Risk-Enhancing Factors

Family history of premature ASCVD (men age lt55y women lt65 y)

Primary hypercholesterolemia

Metabolic syndrome (increased waist circumference elevated triglycerides

elevated blood pressure elevated glucose and low HDL-C

‒ tally of 3 makes the diagnosis

Chronic kidney disease

Chronic inflammatory conditions

2019 ACCAHA Primary Prevention Guideline Risk Enhancing Factors

Grundy SM et al Circulation 2019139e1082-e1143


History of premature menopause (before age 40 y) and history of pregnancy-

associated conditions that increase later ASCVD risk such as preeclampsia

High-risk raceethnicity

Lipids (LDL-C gt ) biomarkers

Persistently elevated primary hypertriglyceridemia

If measured Elevated high-sensitivity C-reactive protein Elevated Lp(a) ndash A STRONG CASE can be made for measuring this at least ONCE in everyone levels gt 125 nmolL ( 100 ) = HIGH RISK patient Elevated apoB (SHOULD BE MEASURED IN MOST PATIENTS apoB app apoB algorithm (A Sniderman) ABI

2019 ACCAHA Prevention Guideline Risk Enhancing Factors contrsquod

Grundy SM et al Circulation 2019139e1082-e1143 Nat Clin Pract Endocrinol Metab 2008 Nov4(11)608-18 doi 101038ncpendmet0982 Epub 2008 Oct 7A diagnostic algorithm for the atherogenic apolipoprotein B dyslipoproteinemias

de Graaf J1 Couture P Sniderman A

Assessment of Subclinical Atherosclerosis for the Non-Cardiologist

Recommended in the new AHA ACC guidelines (ldquoIf risk decision is uncertain Consider measuring coronary artery calcium (CAC) in selected adultsrdquo) CAC = zero (lower risk consider no statin unless diabetes family history of premature CHD or cigarette smoking are present) CAC = 1-99 favors statin (especially after age 55) CAC = 100+ andor ge75th percentile initiate statin therapy

Standard Carotid IMT offers little additional predictive power over traditional risk factorshelliphelliphelliphelliphellipBUThellip

Ultrasound carotid assessment of Total Plaque Volume (TPV) and ldquoPlaque Scorerdquo DOES add predictive risk value similar to CAC ( of focal carotid plaques gt= 15 mm )

In the MESA trial a ldquoplaque scorerdquo of 2-6 increased risk of CHD almost as much as a CAC score 100-399

ECAQ (extracranial carotid atherosclerosis assessment ) technique developed by Drs Thomas Barringer (N Carolina) and Dr Pokrywka (Baltimore) incorporates both TPV estimate and ldquoplaque scorerdquo

Assessment of Subclinical Atherosclerosis for the Non-Cardiologist- Practical Pearls

Do NOT repeat the CAC in patients ON a statin It may go UP confusing patient and clinician ( as LIPID portion of plaque shrinks from statin of plaque that is calcified goes UP increasing the Agatston CAC score)

General consensus is that CAC score is ldquogood forrdquo about 5 years for risk assessment

ECAQ probably BETTER than CAC for younger patients and women and MAY possibly be useful for serial assessment of therapeutic treatment

BOTH techniques ( CAC amp ECAQ) seem to increase patient motivation to change lifestyle and achieve lipidlipoprotein goals

ECAQ easily done in office and involves NO radiation However not yet widely available and needs uniform specific tech training

CAC done in most hospitals and involves small does of radiation MESA risk score app incorporating CAC available for both Iphone and Android

Using The CAC Score to Guide Statin Therapy

bull A CAC score predicts ASCVD events in a graded fashion

ndash 0 useful for reclassifying patients to a lower-risk group often allowing statin therapy to be withheld or postponed unless higher risk conditions are present

ndash 1-99 favors statin therapy

ndash 100+ initiate statin therapy

bull For patients gt75 years of age RCT evidence for statin therapy is not strong so clinical assessment of risk status in a clinicianndashpatient risk discussion is needed for deciding whether to continue or initiate statin treatment

bull European Society of Cardiology guidelines also supports the use of CAC

ndash ldquoCAC score assessment with CT should be considered as a risk modifier in the CV risk assessment of asymptomatic individuals at low or moderate riskrdquo

Grundy SM et al Circulation 2019139e1082-e1143 Atherosclerosis 2019290140-205

Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable

High-intensity statin

(Goal darrLDL-C ge50)

2018 AHAACCAACVPRAAPAABCACPMADAAGSAPhAASPCNLAPCNA

Guideline on the Management of Blood Cholesterol Secondary Prevention


Age le75 y Age gt75 y

Clinical ASCVD

Healthy Lifestyle

ASCVD not at very high-risk

Grundy SM et al Circulation 2018Nov 10 [Epub ahead of print] Although high TG was noted as a CVD risk factor treatment of HTG was covered only briefly and prescription omega-3 was not mentioned (Published simultaneously with REDUCE-IT)

ACS hx of MI stable or unstable

angina coronary or other arterial

revascularization stroke transient

ischemic attack (TIA) or peripheral

artery disease (PAD) including

aortic aneurysm all of

atherosclerotic origin

Class I (Strong) Benefit gtgtgt Risk

Class IIa (Moderate) Benefit gtgt Risk

Class IIb (Weak) Benefit Risk

Very high-risk ASCVD Shown on next slide

Major ASCVD Events Recent ACS

History of MI

History of ischemic stroke

Symptomatic peripheral arterial disease

High-Risk Conditions Age ge65 y

Heterozygous familial hypercholesterolemia

History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)

Diabetes mellitus

Hypertension

CKD

Current smoking

Persistently elevated LDL-C (LDL-C ge100 mgdL) despite maximally tolerated statin therapy and ezetimibe

History of congestive HF

Very high risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions

Grundy SM Stone NJ et al AHAACCMulti-Society 2018 Chol Guidelines Circulation 2019139e1082-e1143

Very High-Risk ASCVD Patients

If on maximal statin

and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add

ezetimibe to maximal

statin before adding

PCSK9-I

IF on clinically judged maximal LDL-C lowering therapy and LDL-C ge70 mgdL or non-

HDL-C ge100 mgdL adding PCSK9-I is reasonable

Dashed arrow

indicates RCT-

supported efficacy but

is less cost effective


Guideline on the Management of Blood Cholesterol Secondary Prevention (cont)


Clinical ASCVD

Healthy Lifestyle


Shown on prior slide Very high-risk ASCVD

High-intensity or maximal statin


Includes a hx of multiple

major ASCVD events or 1

major ASCVD event and

multiple high-risk conditions




Statin Therapy Adjuncts Proven to Reduce ASCVD

Major inclusion criteria for each trial

ACS=acute coronary syndrome ASCVD=atherosclerotic cardiovascular disease

After Orringer CE Trends in Cardiovasc Med 2019 May 4 [Epub ahead of print]

Journal of Clinical Lipidology 2019 13 860-872DOI (101016jjacl201910014)

Acute coronary syndrome

within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)

+ PCSK9I =Alirocumab

or Evolocumab Maximized Statin

Therapy

Stable ASCVD or Diabetes +

1 additional risk factor

Stable ASCVD + additional risk

factors or ACS within 1-12

months

68 OF PATIENTS IN THE United States WITH ESTABLISHED

ASCVD have an LDLC_C gt 70 mgdl despite statinezetimibe

therapy yet only 02 of these patients have ever been Rxrsquod

with a PCSK9i =

PCSK9i are VASTLY under-utilized

Further LDL-C Lowering with Statin Adjuncts Further Reduce MACE (Recent CVOTs)

NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3

CI=confidence interval Cor Revasc=coronary revascularization EZ=ezetimibe HR=hazard ratio MACE=major adverse cardiovascular events

MI=myocardial infarction NNT=number needed to treat Simva=simvastatin UA=unstable angina

1 Cannon CP et al N Engl J Med 20153722387-97

2 Sabatine MS et al N Engl J Med 20173761713-22

3 Steg PG Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab - ODYSSEY OUTCOMES

March 10 2018 httpwwwaccorglatest-in-cardiologyclinical-trials201803090802odyssey-outcomes

Eve

nt R

ate

In IMPROVE-IT the benefit

of adding ezetimibe to

statin was enhanced in patients

With DM and in high-risk

patients without DM

Enhancing the value of PCSK9

Monoclonal antibodies by identifying

patients most likely to benefit A

consensus statement from the

National Lipid Association

Jennifer G Robinson MD MPH et

alJournal of Clinical Lipidology (2019)

13 525ndash53

ldquoTo date most data from clinical trials and genetic studies which together form a stronger evidence base than observational studies do not support a causal link between low LDL-C level and hemorrhagic stroke Several meta-analysis of randomized controlled trials have found no association of statins and hemorrhagic stroke risk Instead a reduction in all-cause stroke and mortality was found Thus if any association for hemorrhagic stroke was present it is likely to be very small and outweighed by the significant benefit of statins on reducing ASCVD eventsrdquo

ldquoThe ODYSSEY Outcomes trial findings are reassuring from a dosendashresponse standpoint If the hypothesis is that low LDL-C level increases hemorrhage stroke risk then one would expect the signal to become stronger in PCSK9 inhibitor trials where the LDL-C has been driven lower than in prior statin trialsYet now we have data from the FOURIER trial and the ODYSSEY Outcomes trial that do not exhibit any dosendashresponse connection This evidence is not only reassuring with respect to use of PCSK9 inhibitors but also from a mechanistic standpoint as it points away from the causal connection between low LDL-C and hemorrhagic strokerdquo

MichosE and Martin S Circulation 20191402063ndash2066 DOI 101161CIRCULATIONAHA119044275

Recent Genetic Studies Do Support Causality of Triglyceride-rich Lipoproteins in CV Risk

bull Apolipoprotein A5

bull Apolipoprotein C3

bull ANGPTL4

bull ANGPTL3

bull Lipoprotein lipase

ANGPTLs=angiopoietin-like proteins Apo=apolipoprotein HL=hepatic lipase LPL=lipoprotein (Lp) lipase TG=triglyceride(s) VLDL=very-low-density Lp Khetarpal SA Rader DJ Arterioscler Thromb Vasc Biol 201535e3-e9

Plasma TG Metabolism

Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL

Apo C-III Hepatic Lipoprotein Receptors

LPL

LPL

HL

Atherosclerotic Plaque

ANGPTLs

Rip J et al Arterioscler Thromb Vasc

Biol 2006261236-45 Plutzky PNAS

2006 Johansen et al J Lipid Res

201152189-206Voight BF et al Lancet

2012380572-80 Nordestgaard BG

Varbo A Lancet 2014384626-35 TG

and HDL Working Group of the Exome

Sequencing Project National Heart

Lung and Blood Institute N Engl J Med

201437122-31 Wang J et al Nat Clin

Pract Cardiovasc Med

2008doi101038ncpcardio1326

Hansen SEJ et al Clin Chem 201965321-332

Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C

Triglyceride-rich Lipoproteins Promote Inflammation Much More than Does LDL

Copenhagen General Population Study + Copenhagen City Heart Study

Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10

Plasma Triglycerides

N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio

n Does atherosclerosis come in different flavors Combined hyperplipidemia (CHL) patients

experienced MI presumably due to plaque rupture or erosion at perhaps half the total burden of

coronary atherosclerosis as the HeFH patients HeFH and CHL obviously differ due to elevation of

triglycerides in CHL Does something high triglycerides lead to vulnerable coronary plaques

at an earlier stage of atherosclerosis development There is evidence that combined dyslipidemia

patients have more inflammation in their plaques and have more low-attenuation plaque ( MORE

rupture prone plaque) than those plaques in patients with pure LDLC elevations

Guyton J Jnl Clin Lipidology MayndashJune 2019Volume 13 Issue 3 Pages 341ndash342

HTG Predicted Additional ASCVD Risk Despite LDL-C at Goal on Statin Monotherapy

Despite achieving LDL-C lt70 mgdL with a high-dose statin

patients with TG ge150 mgdL have a 41 higher risk of coronary events

Death myocardial infarction or recurrent acute coronary syndrome PROVE-IT-TIMI 22

Miller M et al J Am Coll Cardiol 200851724-30

0

5

10

15

20

25

+41

ge150 mgdL lt150 mgdL

On-treatment TG 30-d

ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117

Prevalence of Hypertriglyceridemia (Triglycerides 150 mgdL) in the US

9593 US adults aged gt20 years (2199 million projected) in the US National Health and Nutrition Examination Surveys 2007-2014 were studied

Fan W et al J Clin Lipidol J Clin Lipidol 201913100-108

0

10

20

30

40

50

60

All Statin Treated Not Statin Treated

Millions

Percent

Three Possible Mechanisms for High

ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG

1 Elevated TG Leads to Smaller Denser LDL Particles

LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL

Vascular Wall Macrophage

LDL

Saeed A et al J Am Coll Cardiol 201872156-69 Miller M J Am Coll Cardiol 201872170-2

Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids

uarr Vascular cell adhesion molecule-1

Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC

In HTG TGRL can deliver

more cholesterol per

particle to macrophages

than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation

Leukocyte recruitment

Inflammation

P Libby 2019

2 Triglyceride-rich Lipoproteins May Promote Artery-Wall Inflammation

Monocyte

Macrophage

3 Elevated TG Concurrent Non-lipid Factors That May Drive CVD Risk

After Reiner Ž Nat Rev Cardiol 201714401-11

bull Coagulation factors

bull Impairment of fibrinolysis

bull Pro-inflammatory factors

bull Endothelial dysfunction

Large Clinical Trials of Statin Adjuncts Ezetimibe PCSK9

Inhibitors Fibrates Niacin and IPE

Positive Studies Negative Studies

IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH

Extended-release niacin

HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

Cannon CP et al N Engl J Med 20153722387-97 2 Sabatine MS et al N

Engl J Med 20173761713-22 3 Schwartz GG et al N Engl J Med

20183792097-107 Bhatt DL et al N Engl J Med 201938011-22

ACCORD Study Group et al N Engl J Med 20103621563-74 Keech A et al

Lancet 20053661849-61 Boden WE et al N Engl J Med 20113652255-67

HPS2-THRIVE Collaborative Group N Engl J Med 2014371203-12

Statin and Other Combination Therapy

bull Combination therapy (statinfibrate) has not been shown to improve ASCVD

outcomes and is generally not recommended (A)

bull Combination therapy (statinniacin) has not been shown to provide additional

cardiovascular benefit above statin therapy alone may increase the risk of stroke with

additional side effects and is generally not recommended (A)

bull For patients with diabetes and ASCVD if LDL cholesterol is ge70 mgdL on

maximally tolerated statin dose consider adding additional LDL-lowering

therapy (such as ezetimibe or PCSK9 inhibitor) (A)

‒Ezetimibe may be preferred due to lower cost

(A)= High evidence


Aung T et al JAMA Cardiol 20183225-34

Bhatt DL et al N Engl J Med 201938011-22

Study (Year) EPADHA

Dose (mgd) EPA DHA Source

DOIT (2010) 1150 800 Dietary supplement

AREDS-2 (2014) 650 350 Dietary supplement

SUFOLOM3 (2010) 400 200 Dietary supplement

JELIS (2007) 1800 0 Pure EPA Rx

Alpha Omega

(2010) 226 150

Margarine with dietary supplement

OMEGA (2010) 460 380 Rx EPADHA

RampP (2013) 500 500 Rx EPADHA

GISSI-HF (2008) 850 950 Rx EPADHA

ORIGIN (2012) 465 375 Rx EPADHA

GISSI-P (1999) 850 1700 Rx EPADHA

VITAL (2018) 465 375 Rx EPADHA

ASCEND (2018) 465 375 Rx EPADHA

REDUCE-IT (2018) 4000 0 Rx EPA

20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio

Coronary Heart Disease

Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic

UnderclassifiedOther

Any

Revascularization

Coronary

Noncoronary

Any

Any major vascular event

0 05

Lack of Apparent Effect of OM-3 on ASCVD May be Due to Low Doses Use of Dietary Supplements or Lack of HTG Subjects

15

JELIS Rx EPA Reduced Major Coronary Events in Hypercholesterolemic Patients on Statins and HTG Subgroupdagger

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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19

N=18645 Japanese pts with TC ge251 mgdL prior to baseline statin Rx

Baseline TG=153 mgdL 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

Yokoyama M et al Lancet 20073691090-8

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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group

Control group ndash53

HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0

HR and P-value adjusted for age gender smoking diabetes and HTN

dagger Pre-specified

Saito Y et al Atherosclerosis 2008200135-40

Hi trigslow HDL-C (= metsyn) group

8179 Adults with

bull Well-controlled LDL-C with a statin

bull TG 135-499 mgdL

First occurrence of a Major Adverse CV event

(5-point MACE)

(Nonfatal MI nonfatal

stroke CV death coronary revascularization UA

requiring hospitalization)

First occurrence of a Major Adverse CV

event (3-point MACE)


stroke CV death)

29

Population Primary Endpoint Secondary Endpoint

R

Statindagger + VASCEPA (IPE) 4 gd

Statindagger + placebo

Placebo-Controlled Double-Blind Trial

Median follow-up 49 years

71

REDUCE-IT was Sponsored by Amarin Pharma Inc and Its Affiliates and Conducted Under a Special Protocol Assessment Agreement

with the FDADagger

REDUCE-IT Evaluated Outcomes in Patients With CV Risk Factors

Receiving Statin-Based Standard-of-Care Therapy12

42

ge45 years old

+ established

CVD

ge50 years old +

diabetes

+ ge1 additional CV risk

factor

REDUCE-IT Primary and Secondary Endpoints

Icosapent Ethyl

230 Placebo

283

Years since Randomization

Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001

RRR = 248 ARR = 48 NNT = 21 (95 CI 15ndash33)

Hazard Ratio 075 (95 CI 068ndash083)


Primary End Point CV Death MI Stroke

Coronary Revascularization Unstable Angina


RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

Key Secondary End Point CV Death MI Stroke

USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR

All-Cause Mortality (USA Subset)

HR = 070 (95 CI 055-090)

P=0004

Total (First and Subsequent) Events Primary CV Death MI Stroke Coronary Revasc Unstable Angina

Primary Composite Endpoint

0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05

Placebo Total Events

Icosapent Ethyl Total Events

Placebo First Events

Icosapent Ethyl First Events

HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036


Omega-3 Fatty Acid Molecular Structure

Not for

TG-lowering

Effective for

TG-lowering

1 Arterburn LM et al Am J Clin Nutr 2006831467S-76S Graphic with permission from Mozaffarian D Wu JH J Am Coll Cardiol 2011582047-67

PUFA=polyunsaturated fatty acid 2Rimm EB et al Circulation 2018 Jul 3 138(1) e35ndashe47

ALA has poor conversion

to EPA (03ndash8) and

DHA (lt1) in humans1

Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish

(particularly fatty fish)

per week

A serving is 35 ounce

cooked or about frac34 cup

of flaked fish

Fatty fish like salmon

mackerel herring lake

trout sardines and

albacore tuna are high

in n-3 PUFA2

Reported Clinical and Biologic CV Benefits of Fish Oils Rich in

Omega-3 FA

Anti-arrhythmic

Sudden death (GISSI-P only)

Protection against ventricular arrhythmias (vs )

Heart rate variability improvement

Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons

VLDL and Chylomicron remnants

HDL-C levels (vs w EPA-only)

LDL and HDL particle size

Plaque stabilization

Antithrombotic

Platelet aggregation

Blood rheologic flow

Anti-inflammatory and endothelial

protective effects

C-reactive protein (CRP)

Endothelial adhesion molecules

Leukocyte adhesion receptor expression

Proinflammatory eicosanoids

Proinflammatory leukotrienes

Vasodilation

Systolic and diastolic BP

AF=atrial fibrillation CV=cardiovascular FA=fatty acid(s) After Nelson JR et al Vascul Pharmacol 2017911-9 After Bays HE Chapter 21 The John Hopkins

Textbook of Dyslipidemia by Peter O Kwiterovich 2010 245-57

Adapted with permission from Mason RP Jacob RF Biochim Biophys Acta 20151848502-509 [httpscreativecommonsorglicensesorgby-nc40]

EPA but not Other TG-lowering Agents Inhibit Lipid Oxidation amp Cholesterol Domain Formation

DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin

Bays HE et al Am J Cardiovasc Drugs 20131337-46 Dunbar RL et al Lipids Health Dis 20151498 Ridker PM et al N Engl J Med 20083592195-207

Bohula EA et al Circulation 20151321224-33 Pradhan AD et al Circulation 2018138141-9

Ezetimibe

Ezetimibe + Statin

Omega-3s and Other Lipid Lowering Therapies Have Different

Effects on hsCRP

PCSK9i + Statin

Upcoming CV Outcomes Trials in Patients with HTG

Reported Stopped for futility

Jan 13 2020 Ongoing

REDUCE-IT STRENGTH PROMINENT

Agent

Dose

EPA (EE)

4 gd

550 mg EPA+200 mg DHA

(FFA) in 1-g capsule 4 gd

SPPARMα ndash Pemafibrate

02 mg bid

N 8179 Estimated 13000 Estimated 10000

Age ge45 years ge18 years ge18 years

Risk Profile CVD (70) or

uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)

Follow-up 49 years 3ndash5 years (planned) 5 years (planned)

Statin Use 100 (at LDL-C goal) 100 (at LDL-C goal) Moderate- high-intensity or

LDL lt70 mgdL

Primary Endpoint Expanded MACE Expanded MACE Expanded MACE

Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL

lt40 mgdL M lt45 mgdL W

200ndash499 mgdL

le40 mgdL

Locations International sites Statistics Powered for 15 RRR

REDUCE-IT Bhatt DL et al N Engl J Med 201938011-22 STRENGTH NCT02104817 PROMINENT NCT03071692

X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY

Fish Oil Dietary Supplements Are Widely Used

bull Not over-the-counter but unregulated dietary supplements

bull Estimated global market for omega-3 products was $31 billion in 2015

bull In a large UK prospective study 31 of adults reported taking fish oils

bull Estimates suggest 78 of US population (19 million people) take fish

oil supplements

bull Benefits claimed on the heart brain weight vision inflammation skin

pregnancy and early life liver fat depression childhood behavior

mental decline allergies boneshellip

Many Issues Identified on Leading US Fish Oil Supplements

Mason RP Sherratt SCR Biochem Biophys Res Commun 2017483425-429 Hilleman D and Smer A Manag Care 20162546-52 Albert BB et al Sci Rep

201557928 Kleiner AC et al J Sci Food Agric 2015951260-7 Ritter JC et al J Sci Food Agric 2013931935-9 Jackowski SA et al J Nutr Sci 20154e30 Rundblad

A et al Br J Nutr 20171171291-8 European Medicines Agency 2018 712678

Dietary

Supplement

Rx Omega-3

Saturated fatty acid content in fish oil supplement results in

solid mass following isolation

bull Up to 36 is saturated fat

bull Omega-3 FA content most often overstated

bull Oxidation risk is high

bull Contamination risk

bull Difficult to achieve high doses for efficacy

1 US Food and Drug Administration wwwfdagovFoodDietarySupplementsdefaulthtm Updated April 4 2016 Accessed Nov 4 2018 2 Hilleman D and Smer A Manag Care 20162546-52

3 Mason RP and Sherratt SCR Biochem Biophys Res Commun 2017483425-9 4 Albert BB et al Sci Rep 201557928 5 Kleiner AC et al J Sci Food Agric 2015951260-7 6 Ritter JC et

al J Sci Food Agric 2013931935-9 7 Jackowski SA et al J Nutr Sci 20154e30 8 Rundblad A et al Br J Nutr 20171171291-8 9 European Medicines Agency 2018 712678

FDA Product Classification1 Food

Clinical TrialsFDA

Pre-Approval1

Not Required

Content amp 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

Use for Treatment of Disease Not Recommended

Ability to reduce ASCVD Not demonstrated

New Society Recommendations for Drug Treatment of Patients with

Hypertriglyceridemia

Society Publication Treatment with Statin and IPE for ASCVD Risk Reduction

American Diabetes

Association (ADA)

10 Cardiovascular disease and risk

management Standards of Medical

Care in Diabetesmdash2019

In patients with ASCVD or other cardiac risk factors

with controlled LDL-C but elevated triglycerides

(135-499)

European Society of

Cardiology (ESC) European

Atherosclerosis Society (EAS)

2019 ESCEAS Guidelines for the

Management of Dyslipidaemias

Lipid Modification to Reduce

Cardiovascular Risk

In high-risk (or above) patients with TG levels between

135-499 mgdL n-3 PUFAs (icosapent ethyl 2x2 gday)

should be considered in combination with a statin


(NLA)

National Lipid Association Scientific

Statement on the Use of Icosapent

Ethyl in Statin-treated Patients with

Elevated Triglycerides and High- or

Very-high ASCVD Risk

For patients 45 years of age or older with clinical ASCVD

or 50 years of age or older with diabetes mellitus requiring

medication and ge1 additional risk factor with fasting TG

135-499 mg dL

American Heart Association

(AHA)

AHA Science Advisory Omega-3

Fatty Acids for the Management of


The use of n-3 FA (4 gd) for improving atherosclerotic

cardiovascular disease risk in patients with

hypertriglyceridemia is supported by a 25 reduction in

major adverse cardiovascular events in REDUCE-IT

ASCVD = atherosclerotic cardiovascular disease LDL-C = low-density lipoprotein cholesterol PUFA = polyunsaturated fatty acids TG = triglyceride

American Diabetes Association [web annotation] Diabetes Care 201942(Suppl 1)S103ndashS123 Retrieved from httpshypisJHhz_lCrEembFJ9LIVBZIw Eur Heart J 2020

Jan 141(1)111-188 Orringer CE et al Journal of Clinical Lipidology November 2019 AHA Science Advisory Skulas-Ray AC et al Circulation 2019140e673ndashe691

Expanded FDA Indication for Eicosapentaenoic Acid (EPA) Published December 2019

bull As an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial

infarction stroke coronary revascularization and unstable angina requiring

hospitalization in adult patients with elevated triglyceride (TG) levels (ge 150 mgdL) and

ndash established cardiovascular disease or

ndash diabetes mellitus and 2 or more additional risk factors for cardiovascular disease (1)

bull As an adjunct to diet to reduce TG levels in adult patients with severe (ge 500 mgdL)

hypertriglyceridemia (1)

bull Limitations of Use The effect of VASCEPA on the risk for pancreatitis in patients with

severe hypertriglyceridemia has not been determined (1)

bull The daily dose is 4 grams per day ( 2 bid WITH FOOD (= within 10 minutes of eating

MAY be taken 4 qd if needed to improve adherence)

httpswwwvascepacomassetspdfVascepa_PIpdf

Most Patients with Diabetes Have At Least Two of These Cardiovascular Disease Risk Factors

bull + Family history

bull Age Men gt45 Women gt55

bull BMIgt25

bull Hypertension

bull Hypercholesterolemia

bull HDL-C lt40 mgdL men lt50 mgdL women

bull Smoking

bull C-reactive protein (CRP) gt30

bull Microalbuminuria (30-300 mg of albumin per 24 hours)

bull Renal Dysfunction (GFR 30-60 mlmin)

bull Ankle-Brachial Index (ABI) lt09 (with or without claudication)

bull Physical inactivity

bull Stress

httpswwwmayoclinicorgdiseases-conditionsheart-diseasesymptoms-causessyc-20353118

httpswwwnhlbinihgovhealth-topicsischemic-heart-disease

httpsmyclevelandclinicorghealthdiseases16898-coronary-artery-disease

Icosapent Ethyl (IPE) Warnings and Precautions

bull Atrial FibrillationFlutter IPE was associated with an increased risk of atrial

fibrillation or atrial flutter requiring hospitalization (REDUCE-IT) The incidence

of atrial fibrillation was greater in patients with a previous history of atrial

fibrillation or atrial flutter

bull Potential for Allergic Reactions in Patients with Fish Allergy IPE contains

ethyl esters of the omega-3 fatty acid eicosapentaenoic acid (EPA) obtained

from the oil of fish It is not known whether patients with allergies to fish andor

shellfish are at increased risk of an allergic reaction to IPE

bull Bleeding IPE was associated with an increased risk of bleeding (REDUCE-IT)

The incidence of bleeding was greater in patients receiving concomitant

antithrombotic medications such as aspirin clopidogrel or warfarin


Adherence to Statin Therapy is Critical

bull Generally well tolerated

ndash gtfrac34 of the general population tolerates statin therapy

ndash 10-20 prescribed report statin intolerance

bull Very effective in the prevention and treatment of ASCVD across all LDL-C levels

bull Adverse events rates are very low

ndash The risk of statin-induced serious muscle injury including rhabdomyolysis is lt01

ndash The risk of serious hepatotoxicity is asymp0001

ndash The risk of statin-induced newly diagnosed diabetes mellitus is asymp02 per year of treatment

bull Perceived vs real effect may play a role as multiple studies show nocebo effect

ndash Psychologically conditioned symptoms as a result of expectations due to achieved

knowledge of drug-related side effects

bull Large (40-70) population discontinue statin therapy within 1-2 years

Toth PP et al Am J Cardiovasc Drugs (2018) 18157ndash173

Newman CB et al Arterioscler Thromb Vasc Biol 2019 Feb39(2)e38-e81

Definition and Managing Statin Intolerance

National Lipid Association (NLA)

lsquolsquoInability to tolerate at least two statins one statin at the lowest starting daily dose and

another statin at any daily dose due to either objectionable symptoms (real or

perceived) or abnormal laboratory determinations which are temporally related to statin

treatment and reversible upon statin discontinuationrsquorsquo1

1 Jacobson TA et al J Clin Lipidol 20148473ndash88 2 Banach M et al Int J Cardiol 2016225184ndash96

Steps to Avoid Statin Intolerance2

bull Very careful physical examination of the patient

bull Assess patient history and risk for drug interactions

bull Exclude all possible risk factors and conditions that might increase

the risk of statin intolerance including the so-called lsquolsquonocebo effectrsquorsquo

Inverse Graded Association between Long-term Statin

Adherence and All-cause Mortality in VA patients with ASCVD

Medication Unadjusted Fully Adjustedb

Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)

a Medication possession ratio (reference is those with MPR gt90 b Adjusted for baseline characteristics including adherence to other cardiac medications age statin intensity sex raceethnicity atherosclerotic cardiovascular

disease diagnosis clinical comorbidities Council of Teaching Hospitals and Health Systems and baseline creatinine vital signs pulse oximetry and weight

Rodriguez F et al JAMA Cardiol 20194(3)206-213

Hazard Ratio (95 CI)

ldquoThere is a substantial opportunity for improvement in the secondary prevention

of ASCVD through optimization of statin adherencerdquo

New Lipid Lipoprotein Lowering Agents on the Horizon

Bempedoic acid- an inhibitor of ATP citrate lyase (inhibits cholesterol synthesis at a different step than statins) CLEAR HARMONY trial in patients with FH or ASCVD showed safety and 18 LDL-C lowering CLEAR OUTCOMES trial is underway Might be especially useful in statin intolerant patients

AKCEA-APO(a)-L RX -Lipoprotein (a) Antisense Oligonucleotide Dose dependent 66 to 92 reduction in lipoprotein (a) up to 78 decrease Mild injection site reactions Phase 3 trials underway in patients with hi Lp(a) and ASCVD and or aortic stenosis

Inclisiran- PCSK9 production specifically in the liver is inhibited by messenger RNA interference Mean LDL-C reduction of up to 75 from baseline to day 84 with duration of LDL-C reduction up to at least 6 months (ldquoVaccine-likerdquo ) Mild localized injection site reactions ORION-4 trial phase 3 trail underway to assess cvd rr reduction Bilen O Ballantyne CM Bempedoic Acid (ETC-1002) an Investigational Inhibitor of ATP Citrate Lyase Current atherosclerosis reports 2016186

Sotirios Tsimikas et al Safety and Efficacy of AKCEA-APO(a)- L to Lower Lipoprotein(a) Levels in Patients With Established Cardiovascular Disease A Phase 2 Dose-Ranging TrialNovember 10 2018 415 PM -

425

PM Late Breaking Abstract AHA Scientific Sessions Chicago Ill USA

Fitzgerald K White S Borodovsky A et al A Highly Durable RNAi Therapeutic Inhibitor of PCSK9 The New England journal of medicine 2016 doi

101056NEJMoa1609243 PubMed PMID 27959715

CLEAR Shows Potential for Bempedoic Acid

Laufs U et al J Am Heart Assoc 20198e011662

345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the

lowest available dose) 21 to bempedoic acid 180 mg or placebo once daily for 24 weeks

Plt0001 vs placebo

NEXLETOL (bempedoic acid) tablets for oral use

Initial US Approval 2020 (22120- AVAILABLE by the end of 32020)

----------------------------INDICATIONS AND USAGE---------------------------

NEXLETOL is an adenosine triphosphate-citrate lyase (ACL) inhibitor

indicated as an adjunct to diet and maximally tolerated statin therapy for the

treatment of adults with heterozygous familial hypercholesterolemia or

established atherosclerotic cardiovascular disease who require additional

lowering of LDL-C (1)

Limitations of Use The effect of NEXLETOL on cardiovascular morbidity

and mortality has not been determined

Author tells patients that Lp(a) is ldquoTHE most badass LDL particlerdquo

Many leading Clinical Lipidologists believe that this should be a once in a lifetime

risk assessment for EVERYONE ( levels in general do not change MAY rise a bit

with menopause) The NLA stopped short of this recommendation

Wilson D et al Journal of Clinical Lipidology (2019) 13 374ndash392

=

(= ADD Ezetimibe or PCSK9i)

ldquoSGLT2i AND GLP-1 RA should be FIRSTLINE TREATMENT FOR T2DM NOT METFORMIN ldquo- Ralph Defronzo MD Metformin does NOT lower insulin levels (high insulin levels CAUSE ASCVD MI

CVASCD NOT high blood sugar ) and does not lower mortality = 4th line drug Remember PIOGLITAZONE THIRD LINE = DOES lower insulin levels prevent ldquopancreatic burnoutrdquo AND

REDUCES ASCVD EVENTS

PRE-DM METSYN PATIENTS refractory to diet exercise = use 15 mg pioglitazone 1000 mg metformin









Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



Virginia Council of Nurse Practitioners

Presentation Title

VCNP Clinical Lipidology Update 2020 New life for Vascular EPA

Updated Clinical Guidelines and Vascular Imaging for Non-Cardiologists

I will not discuss off-label medication uses or investigational use in my presentation

I have financial relationships to disclose

Employer Self

Consultant Esperion

Stockholder

Research Support

Honorarium Speakerrsquos Bureau for Amarin Amgen Sanofi Regeneron





Management












CONCENTRATION )




The ABCs of

Primary

Cardiovascular

Prevention 2019

Update

Mar 21

2019 | Abdulha

mied Alfaddagh

MD Kelly Arps

MD Roger S

Blumenthal MD

FACC Seth Shay

Martin MD MHS

FACC

httpswwwaccor

glatest-in-

cardiologyarticles

201903211439

abcs-of-primary-

cv-prevention-

2019-update-gl-

prevention




eating plans




















ge75 to lt20


ge20

ldquoHigh Riskrdquo

lt5

ldquoLow Riskrdquo

5 to lt75



management



















































Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable







Clinical ASCVD

Healthy Lifestyle















History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg







Management












CONCENTRATION )




The ABCs of

Primary

Cardiovascular

Prevention 2019

Update

Mar 21

2019 | Abdulha

mied Alfaddagh

MD Kelly Arps

MD Roger S

Blumenthal MD

FACC Seth Shay

Martin MD MHS

FACC

httpswwwaccor

glatest-in-

cardiologyarticles

201903211439

abcs-of-primary-

cv-prevention-

2019-update-gl-

prevention




eating plans




















ge75 to lt20


ge20

ldquoHigh Riskrdquo

lt5

ldquoLow Riskrdquo

5 to lt75



management



















































Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable







Clinical ASCVD

Healthy Lifestyle















History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg














CONCENTRATION )




The ABCs of

Primary

Cardiovascular

Prevention 2019

Update

Mar 21

2019 | Abdulha

mied Alfaddagh

MD Kelly Arps

MD Roger S

Blumenthal MD

FACC Seth Shay

Martin MD MHS

FACC

httpswwwaccor

glatest-in-

cardiologyarticles

201903211439

abcs-of-primary-

cv-prevention-

2019-update-gl-

prevention




eating plans




















ge75 to lt20


ge20

ldquoHigh Riskrdquo

lt5

ldquoLow Riskrdquo

5 to lt75



management



















































Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable







Clinical ASCVD

Healthy Lifestyle















History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



The ABCs of

Primary

Cardiovascular

Prevention 2019

Update

Mar 21

2019 | Abdulha

mied Alfaddagh

MD Kelly Arps

MD Roger S

Blumenthal MD

FACC Seth Shay

Martin MD MHS

FACC

httpswwwaccor

glatest-in-

cardiologyarticles

201903211439

abcs-of-primary-

cv-prevention-

2019-update-gl-

prevention




eating plans




















ge75 to lt20


ge20

ldquoHigh Riskrdquo

lt5

ldquoLow Riskrdquo

5 to lt75



management



















































Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable







Clinical ASCVD

Healthy Lifestyle















History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg






eating plans




















ge75 to lt20


ge20

ldquoHigh Riskrdquo

lt5

ldquoLow Riskrdquo

5 to lt75



management



















































Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable







Clinical ASCVD

Healthy Lifestyle















History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg














ge75 to lt20


ge20

ldquoHigh Riskrdquo

lt5

ldquoLow Riskrdquo

5 to lt75



management



















































Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable







Clinical ASCVD

Healthy Lifestyle















History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg
















































Initiation of

moderate- or

high-intensity

statin is

reasonable

Continuation of

high-intensity

statin is

reasonable

If high-intensity

statin not

tolerated use

moderate-

intensity statin

If on maximal

statin therapy

and LDL-C ge70

mgdL adding

ezetimibe may be

reasonable







Clinical ASCVD

Healthy Lifestyle















History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




History of MI






Diabetes mellitus

Hypertension

CKD

Current smoking







and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




and LDL-C

ge70 mgdL adding

ezetimibe is

reasonable

If PCSK9-I is

considered add



PCSK9-I



Dashed arrow

indicates RCT-






Clinical ASCVD

Healthy Lifestyle


















within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg









within 10 days

+ Ezetimibe

+ Eicosapentaenoic

Acid ( IPE)



Therapy





months




with a PCSK9i =



NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




NNT = 50

IMPROVE-IT1

NNT = 67

FOURIER2

ODYSSEY Outcomes3







Eve

nt R

ate





patients without DM








13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg










13 525ndash53







bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg









bull ANGPTL4

bull ANGPTL3




Chylomicron

Small Intestine

Apo A-V

Apo C-III

VLDL

Apo A-V

Apo C-III

Chylomicron

Remnant

Apo C-III

VLDL

Remnant

Apo C-III

LDL


LPL

LPL

HL


ANGPTLs














Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




Plasma LDL-C

0

0

2

77

4

155

6

232

8

309

LDL-C



Pe

rce

nt o

f po

pu

latio

n

0

2

25

3

35

15

15

5

10

4

Pla

sm

a C

-reac

tive p

rote

in

mg

L

0 2 4 6 8 10


N=115734

Median 124 mgdL

mmolL

mgdL 0 176 352 528 704 880

TG

CRP

CRP

0

75

25

5

2

25

3

35

15

4

Pe

rce

nt o

f po

pu

latio














0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg








0

5

10

15

20

25

+41



ay r

isk

of

de

ath

M

I

or

rec

urr

en

t A

CS

(

)

165

117




0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg






0

10

20

30

40

50

60


Millions

Percent


ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




ASCVD Risk with HTG

VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



VLDL-TG

IDL

LPL

IDL-TG


LDL

CETP TG CE

LPLHL

LDL-TG

TG TG

HL

Small dense LDL

LDL

LDL

LDL


LDL


Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



Triglyceride-

rich

lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators

bullNFkB

bullp38 MAP kinase

bullEgr-1

Saturated

Fatty Acids


Endothelial cell

Macrophag

e

Lipases

Putative

transducers

bullTLRs

bullPKC




than LDL

Production of

bullMCP-1

bullIL-8

bullothers

Foam cell

formation


Inflammation

P Libby 2019


Monocyte

Macrophage










IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg












IMPROVE-IT

Ezetimibe

HR=0936

(95 CI 089-099)

P=0016

ACCORD

Fenofibrate

HR=092

(95 CI 079-108)

P=032

FOURIER

Evolocumab

HR=085

(95 CI 079-092)

P=00001

FIELD

Fenofibrate

HR=089

(95 CI 075-105)

P=016

ODYSSEY OUTCOMES

Alirocumab

HR=085

(95 CI 078-093)

P=00001

AIM-HIGH


HR=102

(95 CI 087ndash121)

Log-rank P=079

REDUCE-IT

Icosapent ethyl

HR=075

(95 CI 068ndash083)

P=000000001

HPS2-THRIVE

Extended-release

niacinlaropiprant

HR=096

(95 CI 090ndash103)

Log-rank P=029

















(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg













(A)= High evidence




Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg





Study (Year) EPADHA






Alpha Omega

(2010) 226 150










20

Source

Favors

Treatment

Favors

Control

10

Rate Ratio


Nonfatal MI

CHD death

Any

Stroke Ischemic

Hemorrhagic


Any

Revascularization

Coronary

Noncoronary

Any


0 05


15


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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




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

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Eve

nts

(

)

4

P=0011

Statin + EPA 18gday

Statin only 3

2

1

0

HR (95 CI) 081 (069ndash095)

darr

2 3

ndash19







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

in

cid

en

ce

of

ma

jor

co

ron

ary

eve

nts

(

)

EPA 18 gday group


HR 047

95 CI 023ndash098

P=0043

50

40

30

20

10

0





8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



8179 Adults with




(5-point MACE)







stroke CV death)

29


R





71


with the FDADagger



42

ge45 years old

+ established

CVD

ge50 years old +

diabetes


factor


Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




Icosapent Ethyl

230 Placebo

283


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30

P=000000001







RRR = 265

ARR = 36

NNT = 28 (95 CI 20ndash47)

P=00000006

200

162

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ve

nt

()

0 1 2 3 4 5 0

10

20

30


USA subset (3146

pts) had 31 RR

reduction

AR reduction

=65

NNT =15

HR = 069

(95 CI 059-080)

Plt00001

USA subset

(3146 pts)

had 31 RR

reductionAR

reduction

NNT 22

HR = 069 (95 CI 057-

083) Plt00001

30 RRR


HR = 070 (95 CI 055-090)

P=0004



0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg





0 1


5

Cu

mm

ula

tive

Eve

nts

per

Pa

tie

nt

2 3 4 00

01

02

03

04

06

05





HR 075

(95 CI 068ndash083)

P=000000001

RR 070 (95 CI 062ndash078)

P=000000000036



Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




Not for

TG-lowering

Effective for

TG-lowering






Not for

TG-lowering

Effective for

TG-lowering

The American Heart

Association

recommends eating 2

servings of fish


per week



of flaked fish



trout sardines and


in n-3 PUFA2


Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg




Omega-3 FA

Anti-arrhythmic




Anti-atherogenic

Non-HDL-C

TG and VLDL-C

Chylomicrons





Antithrombotic




protective effects






Vasodilation






DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg





DHA

EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



EPA (4 g)

Statins

Lipid Therapy

EPADHA (4 g)

hsCRP Levels

EPA (4 g) + Statin



Ezetimibe

Ezetimibe + Statin


Effects on hsCRP

PCSK9i + Statin



Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg





Jan 13 2020 Ongoing


Agent

Dose

EPA (EE)

4 gd




02 mg bid




uarrCVD risk (30)

CVD (50) or

uarrCVD risk (50)

T2DM only

CVD (23) or

uarrCVD risk (13)



LDL lt70 mgdL


Entry TG

Entry HDL-C

135ndash499 mgdL

NA

200ndash499 mgdL


200ndash499 mgdL

le40 mgdL



X

THE FAILURE

OF STRENGTH

TRIAL VERY

IMPORTANTLY

SHOWS US

THAT IT WAS

NOT THE DOSE

IN REDUCE-IT

THAT REDUCED

RISK IT WAS

THE EPA ONLY






oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg








oil supplements








Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg







Dietary

Supplement

Rx Omega-3












Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg







Clinical TrialsFDA

Pre-Approval1

Not Required














American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg






American Diabetes

Association (ADA)






(135-499)

European Society of






Cardiovascular Risk





(NLA)









135-499 mg dL


(AHA)



























bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



















bull BMIgt25

bull Hypertension



bull Smoking






bull Stress















































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg














































Possession Ratioa

lt50 136 (134-138) 130 (127-134)

50-69 123 (121-124) 121 (118-124)

70-89 107 (106-107) 108 (106-109)












425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg








425








Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg







Plt0001 vs placebo
















=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg








=














Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg















Practitioner



gpokmdverizonnet

Twitter gpokmd

wwwlipidorg



gregory pokrywka md facp fnla faspc ncmp...wvafp clinical lipidology update 2020: new life for...

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