Hypertriglyceridemia: An UnderratedCause of ASCVD...Crosby, J. (TG & HDL Working Group, NHLBI Exome Sequencing Project) NEJM epub 6/18/14. Odds ratio of CHD of subjects with any of

Eliot A. Brinton, MD, FAHA, FNLA, FACEPast-President, American Board of Clinical Lipidology

President, Utah Lipid CenterSalt Lake City, UT, [email protected]

11th Annual Orange County Symposium on Cardiovascular Disease Prevention

9 November 2019Orange, CA

Hypertriglyceridemia:

An Underrated Cause of ASCVD

Disclosures: Duality of Interest

Dr. Brinton has received:

• Research support from Amarin and Kowa

• Honoraria as consultant/advisor: Akcea, Amarin, Amgen, AstraZeneca, Esperion, Kowa, Medicines Co., Regeneron and Sanofi-Aventis

• Honoraria as speaker: Amarin, Amgen, Kowa, Regeneron and Sanofi-Aventis

HTG An Underrated Cause of ASCVD?

• Hypertriglyceridemia (HTG) prevalence

• HTG association with ↑ASCVD

• Mechanisms by which HTG may cause ASCVD

• Diet and lifestyle for HTG management

• Management of ↑ASCVD in HTG—REDUCE-IT

• Summary and Conclusion

HTG & VHTG Prevalence in US Adults:

Mild-Moderate HTG is Common ~1/3 Population

% of US

Adults

Modified from Christian et al. Am J Cardiol 2011: 107: 891

Fasting TG Level (mg/dL)

~30 million Americans have

“high TG”

(moderate HTG)

~26 million Americans have

“borderline high”

TG

Hypertriglyceridemia (TG > 150 mg/dL),

More Common in Statin-Treated Patients

9593 US adults >20 y/o (219.9 million projected) in the US National Health and Nutrition Examination Surveys 2007-2014.

Fan W et al. J Clin Lipidol. J Clin Lipidol. 2019;13:100-108.

0

10

20

30

40

50

60

All Statin Treated Not Statin

Treated

Millions

Percent

NHANES II (1976-1980)

NHANES III (1988-1994)

NHANES IV(1999-2006)

Ages 20-74

Ages 60-74

Increasing prevalence of hypertriglyceridemia in the US

Cohen J, et al. Poster at 2008 AHA Scientific Sessions.

Ford ES, et al. Arch Intern Med. 2009;169:572-8.

Christian JB, et al. Am J Cardiol. 2011;107:891-7.

0

5

10

15

Hig

h T

G (

%)

2.4 2.3

5.5

3.5

5x

8.7

1.8

2x

Increasing TG Levels Associate with ↑MI Stroke and All-cause Mortality

Hazard ratios by Cox proportional

hazard regression models,

adjusted for age, sex, and trial

group.

Nordestgaard BG et al. Lancet.

2014;384:626-35.

Copenhagen City

Heart Study and

Copenhagen General

Population Study

89 177 266 354 443 531 620

Non-fasting TG (mg/dL)

89 177 266 354 443 531 620

Myocardial InfarctionN=96,394 (events=3287); Median follow-up 6 years

Ischemic heart diseaseN=93,410 (events=7183); Median follow-up 6 years

Haza

rd r

ati

o (

95

% C

I)

for

myo

ca

rdia

l in

farc

tio

n

Haza

rd r

ati

o (

95

% C

I)

for

all

-ca

us

e m

ort

ali

ty

All-cause mortalityN=98,515 (events=14,547); Median follow-up 6 years

Ischemic strokeN=97,442 (events=2994); Median follow-up 6 years

5

4

3

2

1

0

5

4

3

2

1

0

4

3

2

1

0

5

4

3

2

1

0

5

Haza

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ati

o (

95

% C

I)

for

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mic

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dis

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se

Haza

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95

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Non-fasting TG (mg/dL)

Stronger Association of Plasma TG (non-fasting) with

MI and All-cause Mortality than LDL-C (Danish Population)

82,890 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study

HR

fo

r M

I

Plasma TG cholesterol, mg/dL

0 250 500 750

0

2

4

6

8

10

LDL-C, mg/dL

0 194 387 580

0

2

4

6

8

10Myocardial Infarction

(MI)

All-cause Mortality

Plasma TG cholesterol, mg/dL

HR

fo

r all

-cau

se

mo

rtality

0 250 500 750

0

2

4

6

8

10

LDL-C, mg/dL

0 194 387 580

0

2

4

6

8

10

Hazard ratios (HR, blue line) with 95% confidence intervals (orange dotted lines).

Nonfasting plasma TGs (‘remnant cholesterol ‘) was calculated as nonfasting total cholesterol minus HDL-C minus LDL-C that was calculated as TG/5.

Nordestgaard BG. Circ Res. 2016;118:547-63.

Evidence that HTG Causes ASCVD:

Mendelian Randomization Data

Mendelian Randomization: HTG & ↑LDL-C Associate with ↑ASCVD (while certain HDL-C-related mutations do not)

ASCVD=atherosclerotic CV disease; HR=hazard ratio; IHD=ischemic heart disease; OR=odds ratio; SD=standard deviation; SNP=single nucleotide

polymorphism. Nonfasting plasma TGs (‘remnant cholesterol ‘) was calculated as nonfasting total cholesterol minus HDL-C minus LDL-C that was

calculated as TG/5. Nordestgaard BG. Circ Res. 2016;118:547-63.

Non-fasting TG

HDL cholesterol

LDL cholesterol

15 selected genetic variants Genome-wide, 185 SNPs

1.0 2.0 4.0 0.3 0.60

HR/OR (95% CI) for IHD per

1 mmol/L or

Effect size [β(95% CI)] for IHD

per 1 SD or

N=66,000 (12,000 IHD)

Varbo A et al. J Am Coll Cardiol. 2013;61:427-36.

N=87,000 (22,000 IHD)

Do R et al. Nat Genet. 2013;45:1345-52.

Triglycerides

HDL cholesterol

LDL cholesterol

Apo C-III LoF Mutation →↓CHD (N=110,970, 15 Studies)

Crosby, J. (TG & HDL Working Group, NHLBI Exome Sequencing Project) NEJM epub 6/18/14.

Odds ratio of CHD of

subjects with any of 4

Apo C3 loss-of-function

mutations among

110,970 participants

(34,002 patients with

CHD and 76,968

controls) in 14 studies

Loss-of-function

Apo C-III mutations

associated with:

• 39% ↓ TG

• 40% ↓ ASCVD

Effects of ANGPTL4 Loss-of-function

Mutations on Lipid Levels and CVD

ANGPTL4=Angiopoietin-like 4.

Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. N Eng J Med. 2016;374:1134-44.

ANGPTL4 loss-of-function

mutations were associated w/:

• 35% ↓TG levels and

• 53% ↓ASCVD risk

Noncarriers Carriers

P=0.003

P=0.30

300

200

100 P=0.19

LDL-C HDL-C TG

Lip

id L

evel

(mg

/dL

)

0

Genetic Causes of HTG and VHTGCommon• Familial hypertriglyceridemia (FHTG)

– ↑TG levels only:• HTG from ↑hepatic VLDL production • VHTG from polygenic & environmental ↓lipoprotein

lipase (LPL) activity– Modest ↑ Apo B but ↑ ASCVD risk

• Familial combined hyperlipidemia (FCHL)??– Variable HTG and ↑cholesterol – Mechanism unknown—poss. just more severe FHTG?– ↑ Apo B and ↑ ASCVD risk

Rare• Familial dysbetalipoproteinemia (Type III)• Familial chylomicronemia syndrome (FCS)

– LPL deficiency (monogenic), – Apo C-II deficiency– GPIHBP1 deficiency– Apo A-V mutations– LMF-1 mutations

After Bays HE. In: Kwiterovich PO Jr, ed. Johns Hopkins Text of Dyslipidemia. 1st ed. Lippincott Williams & Wilkins; 2010:245-57.

Mendelian randomization

studies suggest genetic

HTG causes ASCVD, but

genetic testing in HTG is

rarely useful in clinical

practice

Apparent Mechanisms of

↑ASCVD Risk in HTG

VLDL-TG

IDL

LPL

IDL-TG

#1: Elevated TG Leads to Smaller, Denser LDL

Particles

LDL

CETPTG CE

LPL/HL

LDL-TG

TG TG

HL

Small, dense LDL

LDL

LDL

LDL

Vascular Wall Macrophage

LDL

Saeed A et al. J Am Coll Cardiol. 2018;72:156-69. Miller M. J Am Coll Cardiol. 2018;72:170-2.

Triglyceride-

rich lipoprotein

(TGRL)

Apolipoprotein CIII

Cholesterol

Transcriptional

Activators:

•NFkB

•p38 MAP kinase

•Egr-1

Saturated

Fatty Acids

↑ Vascular cell adhesion molecule-1

Endothelial cell

Lipases

Putative

transducers:

•TLRs

•PKC

In HTG, TGRL can deliver

more cholesterol per

particle to macrophages

than LDL

Production of:

•MCP-1

•IL-8

•others

Foam Cell Formation

Leukocyte recruitment

Inflammation

After P. Libby 2019

#2: TG-Rich Lipoproteins May Promote

Artery-Wall Inflammation

Monocyte

Macrophage

#3: Elevated TG: Non-lipid Factors May Drive ↑CVD Risk

After Reiner Ž. Nat Rev Cardiol. 2017;14:401-11.

• ↑Platelet activity

• ↑Coagulation/↓fibrinolysis

• Pro-inflammatory factors

• Endothelial dysfunction

After Peng, J. et al. Lipids in Health and Disease (2017) 16;233.

VLDL

Remnant

Chylomicron

Remnant

Roles of LPL, Apo C3, ANGPTL3 and 4, and

Apo A5 in Plasma Triglyceride Metabolism

ANGPTL=angiopoietin-like protein; HL=hepatic lipase; LPL=lipoprotein lipase.

Khetarpal SA, Rader DJ. Arterioscler Thromb Vasc Biol. 2015;35:e3-9.

Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. N Eng J Med. 2016;374:1134-44.

Hepatic Lipoprotein

Receptors

LDL

LPL, HL

Liver

VLDL

Chylomicron

Small Intestine

Atherosclerotic

Plaque

LPL

Apo C3

Apo C3

Apo C3 Apo C3

Apo C3

Apo A5

Apo A5

ANGPTL4ANGPTL3

↑Triglycerides

↑ Risk of CVD

Reduces LPL activityLPL: loss of function

Apo A5: loss of function

Apo C3: gain of functionIncreases LPL activityLPL: gain of function

ANGPTL4: loss of function

Apo C3: loss of function

↓Triglycerides

↓ Risk of CVD

LPL hydrolyzes

TGs that are

present in

circulating

lipoproteins and

reduces the plasma

TG level

Apo A5 is an

activator of LPL

and enhances the

metabolism of TG-

rich particles

Apo C3 inhibits LPL

activity and increased

levels can induce HTG

If not removed from

circulation, LDL and

remnants may be

taken up by

macrophages in the

arterial wall

Management of

Patients with HTG

Fasting vs Nonfasting Measurements of

TG and Non-HDL-CPros for Non-Fasting Testing (usually easier, “politically correct”)• Nonfasting may better predict ASCVD (population only, not individual)• Nonfasting TG is similar to fasting after a low-fat meal (eg, <15 g fat), but will

↑ > 50% after high-fat meal (eg, 50g fat)• “Big-Mac” tolerance test? • Non-HDL-C is accurate fasting or nonfasting, and is the best basic lipid

predictor of CVD risk in patients w/ HTG*Pros for Fasting Testing (usually better, might be easier)• Best to categorize TG elevation in general • Best TG (for metabolic syndrome)• Best glucose (for metabolic syndrome)• Data in-hand at clinic visit (if done beforehand)• If nonfasting TG is ≥200 mg/dL need to do a fasting TG anyway

*Modified from: NLA Recommendations. Jacobson TA et al. J Clin Lipidol. 2014;8:473-88 and AHA Scientific Statement. Miller M et al. Circulation. 2011;123:2292-333.

Classification of Fasting TG Levels (2011 AHA/2014 NLA)

Jacobson TA et al. J Clin Lipidol. 2014;8:473-88.

American Heart Association (AHA) Scientific Statement. Miller M et al. Circulation. 2011;123:2292-333.

Fasting Triglycerides (mg/dL)

<100 Optimal

<150 Normal

150–199 Borderline high

200–499 High

500 Very high

Always Treat Secondary Causes of HTG

*Strong dose-gene interaction (polygenic); HIV=human immunodeficiency virus.After Bays HE. In: Kwiterovich PO Jr, ed. Johns Hopkins Text. of Dyslipidemia. 1st ed. Lippincott Williams & Wilkins;2010:245-57 and Hegele R Lancet Diabetes & Endocrin 2014, 2(8)655-666.

Cause Clinically useful details

DietCalories (Saturated fat? glycemic index?), ethanol*

Simple sugars, esp. fructose (sucrose, etc.) & ↓dietary fiber

Adiposopathy Especially if with visceral adiposity

Diabetes mellitus Especially if insulin resistant and/or hyperglycemic

Hypothyroidism Only if inadequately controlled

Renal disease Nephrotic syndrome, ESRD, glomerulonephritis

Systemic Inflammation Lupus, rheumatoid arthritis, paraproteinemias, etc.

Medications

Antiretroviral agents (for HIV), asparaginase (for leukemia)2nd-generation anti-Ψ, phenothiazines, anti-seizure medsNonselective beta-blockers & thiazide diuretics Bile-acid sequestrantsPregnancy (especially 3rd trimester)Oral contraceptives, oral hormone replacement, tamoxifenGlucocorticoids and isotretinoin

Recreational drugs Ethanol*, marijuana (ApoC-III)

Lifestyle and Diet Can Have Big Benefits in Hypertriglyceridemia

Diet / Lifestyle Change Lipid Profile Change

Weight loss in overweight or obese

individuals (>5–10%)TG (20%), LDL-C (15%) & HDL-C

(10%)

Diet

Grains, vegetables & low-fat dairy

Sugars (milk-sugar N/A, total

carb)

Total fat (for TG > 800 only)

Ethanol

Exercise, e.g. brisk walk 30 min, 3/wkTG (variable, depends on baseline

TG)

Modified from Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

Sampson UK et al. Curr Atheroscler Rep. 2012;14:1-10.

TG (10-20%)

20% - 50% TG possible

w/ Lifestyle Interventions

(especially weight loss

and very-low-fat for TG

>800)

Is HTG an ASCVD Risk Factor When

LDL-C is controlled

on a Statin?

YES

Residual HTG Predicts Residual ↑CV Risk* Despite Well Controlled LDL-C on Statin Monotherapy

Despite LDL-C <70 mg/dL on a statin

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

Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

0

5

10

15

20

25

↑41%

CVD Risk*

≥150 mg/dL <150 mg/dL

On-treatment TG

AS

CV

D R

isk*

(%)

16.5%

11.7%Several CVOTs

have shown

similar findings

HTG Associated w/↑ASCVD, Hospitalization & Costs (Despite LDL-C ~104 mg/dL on a Statin)

HTG: ↑ASCVD, Hospital Stays & Medical Costs*,† TG 200-499 vs TG < 150*

*Retrospective administrative claims, ≥45 y/o w/ diabetes and/or ASCVD on a statin, with TG 200–499 mg/dL (n=13,411) vs comparator control (TG <150 mg/dL and HDL-C >40 mg/dL, n=32,506). Baseline LDL-C 106 and 101 mg/dL, respectively (p<0.001), cohorts propensity-score matched for age, gender, insurance, region, baseline clinical characteristics and meds.†Cox proportional hazards model was used for all multivariate analyses except “Total Healthcare Costs,” which used a generalized linear model.

Toth PP et al. J Am Heart Assoc. 2018;7:e008740. DOI: 10.1161/JAHA.118.008740.ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; HTG, high triglycerides; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiac event; MI, myocardial infarction; NS, not significant.

35% Major

CV Event Rate

15% Total

Healthcare Costs

17% Hospital

Stays

HTG Associated w/↑ASCVD, Hospitalization & Costs (Despite LDL-C ~104 mg/dL on a Statin)

HTG: ↑ASCVD, Hospital Stays & Medical Costs*,† TG 200-499 vs TG < 150*

*Retrospective administrative claims, ≥45 y/o w/ diabetes and/or ASCVD on a statin, with TG 200–499 mg/dL (n=13,411) vs comparator control (TG <150 mg/dL and HDL-C >40 mg/dL, n=32,506). Baseline LDL-C 106 and 101 mg/dL, respectively (p<0.001), cohorts propensity-score matched for age, gender, insurance, region, baseline clinical characteristics and meds.†Cox proportional hazards model was used for all multivariate analyses except “Total Healthcare Costs,” which used a generalized linear model.

Toth PP et al. J Am Heart Assoc. 2018;7:e008740. DOI: 10.1161/JAHA.118.008740.ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; HTG, high triglycerides; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiac event; MI, myocardial infarction; NS, not significant.

35% Major

CV Event Rate

15% Total

Healthcare Costs

17% Hospital

Stays

Several other

observational studies

have shown

similar findings

Prevention of ASCVD in HTG Patients

JELIS: EPA Reduced Major Adverse Coronary Events (MACE)*

in Hypercholesterolemic Patients on Statins

Yokoyama M et al. Lancet. 2007;369:1090-8.

No. at Risk

Control

EPA

0 1 4 5 Years

9319 8931 8671 8433 8192 7958

9326 8929 8658 8389 8153 7924

Cu

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f M

ajo

r

Co

ron

ary

Even

ts

(%)

4

P=0.011

Statin + EPA 1.8g/day

Statin only3

2

1

0

HR (95% CI): 0.81 (0.69–0.95)

↓

2 3

N=18,645 Japanese pts with TC ≥251 mg/dL prior to baseline statin Rx. Baseline TG=153 mg/dL.

Statin up-titrated to 20 mg pravastatin or 10 mg simvastatin for LDL-C control.

*Primary endpoint: sudden cardiac death, fatal and non-fatal MI, unstable angina pectoris,

angioplasty, stenting, or coronary artery bypass graft.

RRR

–19%

*Pre-specified analysis in primary prevention subjects. MACE=major adverse CV event.

Saito Y et al. Atherosclerosis. 2008;200:135-40.

JELIS: Larger Decrease in MACE in Subjects with

TG >150 mg/dL & HDL-C <40 mg/dL*

HR and P-value

adjusted for age,

gender, smoking,

diabetes, and HTN

No. of patients

Control 475 444 432 414 400 392

EPA 482 455 443 427 413 403

0 1 2 3 4 5 Years

Cu

mu

lati

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ncid

en

ce o

f m

ajo

r

co

ron

ary

even

ts (

%)

EPA 1.8 gm/day group

Control group

RRR

–53%

HR: 0.47

95% CI: 0.23–0.98

P=0.043

5.0

4.0

3.0

2.0

1.0

0

Omega-3 CV Outcome Trial Meta-Analysis:

No ↓CVD w/ Low-dose EPA+DHA Mix; ↓CVD w/ Mid-dose Pure EPA

REDUCE-IT Design

1. Age ≥45 y with established CVD (2o Prevention)

or high risk 1o prevention: ≥50 y with diabetes +

≥1 additional CVD risk factor

2. Fasting TG levels 135-500 mg/dL

3. LDL-C 40-100 mg/dL and on stable statin Rx (±

ezetimibe) for ≥4 weeks prior to qualifying

measurements for randomization

Primary Endpoint Events: CV death, nonfatal MI, nonfatal stroke, coronary revasc, hospitalization for unstable angina

Key Secondary Endpoint Events: CV death, nonfatal MI, nonfatal stroke

Double-blind study; Events adjudicated by CEC that was blinded to treatment during adjudication

Screened

N=19,212

Randomized

N=8179

(43% of screened)

Icosapent Ethyl

4 grams/day

N=4089

Placebo

N=4090

Known vital status 4083 (99.9%) Known vital status 4077 (99.7%)

Median trial

follow up

4.9 yr

Bhatt, DL, Steg PG, Brinton, EA. Clinical Cardiology. 2017;40:138–148 and Bhatt DL, Steg PG, Miller M, et al. NEJM. 2019; 380:11-22.

REDUCE-IT Design “Firsts”:Among contemporary, statin-adjunct Cardiovascular Outcome Trials (CVOTs):• 1st one focused on patients w/ elevated TG• 1st using full-dose prescription omega-3• 1st using full-dose pure EPA (IPE)• 1st using pure EPA with/in:

– Moderate- to high-intensity statin background Rx– Multinational population (5 continents)– Double-blind placebo-controlled design

Bhatt, DL, Steg, PG, Brinton, EA., et al. Clinical Cardiology 2017 Mar;40(3):138-148.

Key Baseline Characteristics

Icosapent Ethyl

(N=4089)

Placebo

(N=4090)

Age (years) 64 64

Female, % 28.4% 29.2%

CV Risk Category, %

Secondary Prevention Cohort 70.7% 70.7%

Primary Prevention Cohort 29.3% 29.3%

Prior Atherosclerotic Cardiovascular Disease, % 68.9% 69.3%

Prior Atherosclerotic Cerebrovascular Disease, % 15.7% 16.2%

Prior Atherosclerotic Peripheral Artery Disease, % 9.5% 9.5%

LDL-C (mg/dL), Median (Q1-Q3) 74.0 (61.5 - 88.0) 76.0 (63.0 - 89.0)

Triglycerides (mg/dL), Median (Q1-Q3) 216.5 (176.5 - 272.0) 216.0 (175.5 - 274.0)

Triglyceride Category (by Tertiles)*

≥81 to ≤190 mg/dL 1378 (33.7%) 1381 (33.8%)

>190 to ≤250 mg/dL 1370 (33.5%) 1326 (32.4%)

>250 to ≤1401 mg/dL 1338 (32.7%) 1382 (33.8%)

Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019. Bhatt DL. ACC 2019, New Orleans.

*Baseline TG calculated as average of final screening TG and subsequent TG value from date of randomization.

Key Background Medical Therapy

Icosapent Ethyl

(N=4089)

Placebo

(N=4090)

Antiplatelet 3257 (79.7%) 3236 (79.1%)

One Antiplatelet agent 2416 (59.1%) 2408 (58.9%)

> 2 Antiplatelets 841 (20.6%) 828 (20.2%)

Anticoagulant 385 (9.4%) 390 (9.5%)

ACEi or ARB 3164 (77.4%) 3176 (77.7%)

Beta Blocker 2902 (71.0%) 2880 (70.4%)

Statin 4077 (99.7%) 4068 (99.5%)

Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.

Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint





Primary End Point:CV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Icosapent Ethyl

23.0%Placebo

28.3%

Years since Randomization

Pa

tie

nts

wit

h a

n E

ve

nt

(%)

0 1 2 3 4 5

0

10

20

30

P=0.00000001

RRR = 24.8%

ARR = 4.8%

NNT = 21 (95% CI, 15–33)

Hazard Ratio, 0.75(95% CI, 0.68–0.83)

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL. AHA 2018, Chicago.

20.0%

16.2%

Icosapent Ethyl

Placebo

Key Secondary End Point:CV Death, MI, Stroke

Hazard Ratio, 0.74(95% CI, 0.65–0.83)

RRR = 26.5%

ARR = 3.6%

NNT = 28 (95% CI, 20–47)

P=0.0000006


Pa

tie

nts

wit

h a

n E

ve

nt

(%)

0 1 2 3 4 5

0

10

20

30


Omega-3 CV Outcome Trials:

No ↓CVD w/ Low-dose EPA+DHA Mix; Yes ↓CVD w/ Mid-dose Pure EPA

REDUCE-IT is 2nd of 2 CVOT’s w/ ↓CVD from EPA as Statin AdjunctTWO Best RRRs of All: JELIS ↓19% and REDUCE-IT ↓25%

Total Mortality 0.87 (0.74–1.02) 0.09

Endpoint

Primary Composite (ITT)

Key Secondary Composite (ITT)

Cardiovascular Death orNonfatal Myocardial Infarction

Fatal or Nonfatal Myocardial Infarction

Urgent or Emergent Revascularization

Cardiovascular Death

Hospitalization for Unstable Angina

Fatal or Nonfatal Stroke

Total Mortality, Nonfatal MyocardialInfarction, or Nonfatal Stroke

310/4090 (7.6%)

Placebo

n/N (%)

901/4090 (22.0%)

606/4090 (14.8%)

507/4090 (12.4%)

355/4090 (8.7%)

321/4090 (7.8%)

213/4090 (5.2%)

157/4090 (3.8%)

134/4090 (3.3%)

690/4090 (16.9%)

274/4089 (6.7%)

Icosapent Ethyl

n/N (%)

705/4089 (17.2%)

459/4089 (11.2%)

392/4089 (9.6%)

250/4089 (6.1%)

216/4089 (5.3%)

174/4089 (4.3%)

108/4089 (2.6%)

98/4089 (2.4%)

549/4089 (13.4%)

Hazard Ratio (95% CI)

0.75 (0.68–0.83)

0.74 (0.65–0.83)

0.75 (0.66–0.86)

0.69 (0.58–0.81)

0.65 (0.55–0.78)

0.80 (0.66–0.98)

0.68 (0.53–0.87)

0.72 (0.55–0.93)

0.77 (0.69–0.86)

P-value

<0.001

<0.001

<0.001

<0.001

<0.001

0.03

0.002

0.01

<0.001

Hazard Ratio

(95% CI)

1.4

Icosapent Ethyl Better Placebo Better

0.4 1.0

Prespecified Hierarchical TestingRRR

23%

28%

32%

20%

35%

31%

25%

26%

25%

13%


REDUCE-IT appendix. Bhatt, DL. NEJM epub Nov 10, 2018

REDUCE-IT: Individual Elements of Primary Endpoint (5-POINT MACE)

Total (First and Subsequent) EventsPrimary: CV Death, MI, Stroke, Coronary Revasc, Unstable Angina


Primary Composite Endpoint

0 1


5

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mm

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ven

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er

Pati

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2 3 40.0

0.1

0.2

0.3

0.4

0.6

0.5

Placebo: Total Events

Icosapent Ethyl: Total Events

Placebo: First Events

Icosapent Ethyl: First Events

HR, 0.75

(95% CI, 0.68–0.83)

P=0.00000001

RR, 0.70(95% CI, 0.62–0.78)

P=0.00000000036

143

126

1,546

901

376

Placebo

[N=4090]

Nu

mb

er

of

Pri

mary

Co

mp

os

ite

En

dp

oin

tE

ve

nts

3rd1st 2nd ≥4

1,076

Icosapent Ethyl

[N=4089]

7263

705

2362nd EventsHR 0.68

(95% CI, 0.60-0.78)

1st EventsHR 0.75

(95% CI, 0.68-0.83) P=0.000000016

≥4 EventsRR 0.52

(95% CI, 0.38-0.70)

3rd EventsHR 0.69

(95% CI, 0.59-0.82)

RR 0.70(95% CI, 0.62-0.78)

P=0.00000000036


Reduced Dataset Event No.

-63

-71

-196

-140

-470

No. ofFewerCases

30% Reduction in Total Events

First and Subsequent Events

Note: WLW method for the 1st events, 2nd events, and 3rd events categories;

Negative binomial model for ≥4th events and overall treatment comparison.

1,600

1,200

800

400

0

600

1,000

1,400

200

Primary

Composite

Endpoint

-159

Cardiovascular

Death

-12

Fatal or

Nonfatal MI

-42 Fatal or

Nonfatal

Stroke

-14

Coronary

Revascularization

-76

Hospitalization

for Unstable

Angina

-16

-100

-150

-200

-50

0

Ris

k D

iffe

ren

ce


For Every 1000 Patients Treated with Icosapent Ethyl for 5 Years:

.

PowerPoint Presentation

Rx EPA (IPE) ↓ASCVD in patients with

baseline TG 135-200 ≈ TG 200-500!

#AHA18: Cholesterol Guidelines full update; omega-3s and CV

events; yoga and risk reduction - Message (HTML)

Rx EPA (IPE) ↓ASCVD in patients with

baseline TG 135-150 ≈ TG 150-500!!

TOTAL EVENTS – Primary Composite Endpoint/Subgroup Icosapent Ethyl Placebo RR (95% CI) P-value

Rate per 1000

Patient Years

Rate per 1000

Patient Years

Primary Composite Endpoint (ITT) 61.1 88.8 0.70 (0.62–0.78) <0.0001

Baseline Triglycerides by Tertiles*

≥81 to ≤190 mg/dL 56.4 74.5 0.74 (0.61–0.90) 0.0025

>190 to ≤250 mg/dL 63.2 86.8 0.77 (0.63–0.95) 0.0120

>250 to ≤1401 mg/dL 64.4 107.4 0.60 (0.50–0.73) <0.0001

Primary Composite Endpoint:Total Endpoint Events by Baseline TG Tertiles

Bhatt DL. ACC 2019, New Orleans.

Placebo

Better

Icosapent Ethyl

Better

1.00.2 1.40.6 1.8 *P (interaction) = 0.17

↓CVD w/ EPA Was Comparable w/ On-Rx TG > vs < 150 mg/dL

Similar results were seen with the key secondary endpoint

Bhatt DL, et al. N Engl J Med. 2019;380(1):11-22.

Did ASCVD↓ More in Subgroup with TG > 200 PLUS HDL-C < 35? Maybe NOT

Subgroup % Subjects w/ CVD Events P-heterogeneity

TG ≥200 mg/dL and HDL-C ≤35 mg/dL

Icosapent Ethyl

Placebo HR (95% CI)0.04

Yes 18.1 27.0 0.62 (0.51-0.77)

No 17.0 20.9 0.79 (0.71-0.88)

Above data are with 1o endpoint, 5-point MACE, but

P-value only 0.50 (NS) for stronger 2o endpoint (“Hard” 3-point MACE)

REDUCE-IT Surprise:

In Mild-Moderate HTG Patients

Baseline & On-Rx TG Levels Don’t Seem to Matter!!

In other words…

Mild-Moderate HTG is an

Indicator of High ASCVD Risk

but NOT a Target of Therapy

(contrast with LDL)

PowerPoint Presentation

(No Difference in Overall TEAE)


EPA Effects on Arrhythmias and Their SequelaeIPE 4g/d Pbo HR (95%CI) P value

Atrial* % N % N

Total Atr. Fibrillation 5.3 215 3.9 159 Sig↑** 0.003

Hosp. for Atr. Fib. 3.1 127 2.1 86 Sig↑** 0.004

Ventricular(?)

Sudden Cardiac Death 1.5 61 2.1 87 .69 (.50-.96) Sig↓**

Cardiac Arrest 0.5 22 1.0 42 .52 (.31-.86) Sig↓**

Total

Arrhyth. Req. Hosp. >24h 4.6 188 3.8 154 1.21 (.97-1.49) NS

*No increases in the worst AFib sequelae: TIA, CHF, dyspnea or fatigue. **Not given.

JELIS provided no information about arrhythmias. See Yokoyama M Lancet 2007;369;1090-98.

EPA+DHA trials/studies sugg: ↑atrial fibrillation (↓if post cardiac surg) vs ↓ventricular events. (see Kowey, PR. JAMA;2010;304:2363-72; Mozaffarian, D. JACC;2011;58:2047-67; von Schacky, C. Frontiers in

Physiol. 2012; 3; 88. Christou, GA. Int J Mol Sci 2015;16: 22870-87 Siscovick, DS. Circul. 2017;135;e867-84.)

Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPointTrend Towards ↑Total Serious Bleeding Events—Likely Real

Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPointBut No Apparent ↑Intracranial or Fatal Bleeding Events

EPA Safety and Tolerability in Long-Term CVOT (JELIS, N=18,645)

CPK=creatine phosphokinase; GOT=glutamic oxaloacetic transaminase *No between-group differences in stroke (incl cerebral or subarachnoid hemorrhage). Hazard ratio for hemorrhagic stroke 1.12 (0.91–1.39, P=0.272).• The rate of discontinuation due to treatment-related adverse effects was 11.7% in the EPA + statin group and 7.2% in the statin only group• Most adverse events attributed to EPA treatment were regarded as mild by the investigators

EPA Group Control P Value

Pain (joint, lumbar, muscle) 1.6% 2.0% 0.04

Gastrointestinal disturbance (nausea, diarrhea, epigastric

discomfort)3.8% 1.7% <0.0001

Skin abnormality (eruption, itching, exanthema, eczema) 1.7% 0.7% <0.0001

Hemorrhage (cerebral, fundal, epistaxis, subcutaneous)* 1.1% 0.6% 0.0006

Abnormal laboratory data

•Total

•CPK increased

•GOT increased

•Blood sugar level increased

4.1%

1.4%

0.6%

0.4%

3.5%

1.2%

0.4%

0.3%

0.03

0.52

0.03

0.17

Yokoyama M et al. Lancet. 2007;369(9567):1090-1098.

63

Plasma EPA w/ EPA 1.8 g/d in Japanese

Comparable to IPE 4 g/d in Non-Japanese

Institute for Clinical and Economic Review, 2019. Draft Evidence Report. Additive Therapies for Cardiovascular Disease: Effectiveness and Value. https://icer-review.org.

IPE is Very Cost-Effective: REDUCE-IT DataA preliminary report from the Institute for Clinical and Economic Review (ICER) on the effectiveness and value of icosapent ethyl• Comparative Clinical Effectiveness

“For adults with established CVD or at high risk of cardiovascular events who are being treated with statins, we have high certainty that icosapent ethyl provides a small-to-substantial net health benefit (“B+”).

• Long-term Cost Effectiveness

Icosapent ethyl (in patients receiving statins) provides clinical benefit in terms of gains in quality-adjusted survival compared to optimal medical management alone in the adult with established CVD cohort and without known CVD but at high risk for CVD events.

This translated into incremental cost-effectiveness estimates that fell below commonly cited cost-effectiveness thresholds under the assumptions used for this analysis, which were willingness-to-pay thresholds of both $50,000 per QALY and $100,000 per QALY gained.

Icosapent ethyl vs. optimal medical management yields $18,000 per QALY gained at the current

wholesale acquisition cost of $303.65 per month.

Cost/QALY much less at:• Cash price of ~$220/mo• Payer price of ~$120/mo

REDUCE-IT:

A Paradigm Shift

in Atheroprevention

Statin Adjuncts Proven to Reduce CVD

*Major inclusion criteria for each trial.

ACS=acute coronary syndrome; ASCVD=atherosclerotic cardiovascular disease.

Modified from Orringer C. Oral Discussion of REDUCE-IT presentation; AHA 2018, Chicago.

Acute coronary syndrome within

10 days*

+ Ezetimibe + Icosapent ethyl+ Alirocumab or

Evolocumab

Statin Monotherapy

Stable CVD; or Diabetes + 1

additional risk factor*

Stable CVD + additional risk

factors; or ACS within 1-12

months*

Outside Expert Summary in response to REDUCE-IT Presentation:

Post-REDUCE-IT Guidelines/Statements:

IPE Decreases CVD Risk

• ADA: Add IPE to statin Rx to ↓ CV risk

• ESC: Add IPE to statin Rx to ↓ CV risk

• NLA: Add IPE to statin Rx to ↓ CV risk

• AHA: Omega-3 Advisory—IPE →25%↓ CV risk

American Diabetes Association (ADA) Guideline update March 2019

European Society for Cardiology (ESC) Guidelines September 2019

National Lipid association (NLA) Statement (press-release September 2019)

American Heart Association (AHA) Statement on Omega-3 Treatment (Skulas-Ray AC, et al.

Circulation. 2019;140: e1-e19)

Conclusion:

IPE Prevents ASCVD

Patients on Statin therapy with:

• TG > 135 mg/dL, despite• Controlled LDL-C (< 100 mg/dL)

At High Risk for CV Events:

• 2o Prevention, and importantly also• High-risk 1o Prev. (e.g. DM + add’l RFs)

RE

DU

CE

-IT

FDA Review of sNDA for CVD Prevention Indication for

Icosapent Ethyl: Mini-history, 2019 (pure EPA/Vascepa)

• Late Spring: September 28 set as PDUFA date, under priority review (no committee meeting planned)

• June 29: Medical Research Collaborative petition to FDA (21 C.F.R. § 10.30 and 21 C.F.R. § 10.31, FDCA) regarding active effects of placebo (light liquid paraffin) in REDUCE-IT—requesting Amarin do new studies

• Early Summer: – EMDAC review scheduled for November 14– PDUFA date postponed to December 28

Summary and Conclusions: ASCVD in HTG Patients

• HTG is common and is associated with ↑ASCVD, even when LDL-C is well controlled with statin Rx

• HTG appears to cause ASCVD– Mendelian randomization– Multiple MoA

• Recognition of high residual ASCVD risk in HTG patients (even on statins) is clinically important

• REDUCE-IT is a “Game Changer”—pure EPA (IPE) is now the statin adjunct of choice in patients with:– LDL-C <100 mg/dL on statin (+/- LDL-C adjuncts), and– TG >135 mg/dL, and– High ASCVD risk– On-treatment TG may not matter

Documents

Hypertriglyceridemia: An UnderratedCause of ASCVD...Crosby, J. (TG & HDL Working Group, NHLBI Exome Sequencing Project) NEJM epub 6/18/14. Odds ratio of CHD of subjects with any of