Hypertriglyceridemia

CVD Risk Assessment

and Management

Strategies in Women

Gregory S. Pokrywka, MD, FACP, FNLA, NCMP

Assistant Professor of Medicine

Johns Hopkins University School of Medicine

Director, Baltimore Lipid Center

Diplomate, American Board of Clinical Lipidology

Baltimore, MD

Prevalence of HTG in NHANES

1999–2008: Overall and by Ethnicity (%)

AHA Scientific Statement. Miller M et al. Circulation. 2011;123:2292-333.

31

16.2

1.1

33

17.6

1.1

15.6

7.6

0.4

34.9

19.5

1.4

0

5

10

15

20

25

30

35

40

TG ≥150 mg/dL TG ≥200 mg/dL TG ≥500 mg/dL

~70 million persons (~1/3 of adult US population) have TG (≥150 md/dL)

Pre

va

len

ce

of

TG

at

or

ex

ce

ed

ing

pre

-sp

ecif

ied

cu

t-o

ffs

(%

)

Overall

Non-Hispanic White

Non-Hispanic Black

Mexican-American

Components, Size, and Density of Human

Serum Lipoproteins

Genest J, Libby P. Lipoprotein Disorders and Cardiovascular Disease. Braunwald’s Heart Disease: a textbook of cardiovascular

medicine, tenth edition. Elsevier 2014, Chapter 45.

Structural components of lipoproteins

Apolipoprotein B

Phospholipid

Triglyceride

Cholesterol

Cholesteryl ester

Apolipoprotein C

Apolipoprotein E

Relation to diameter and density

Chylomicron

VLDL

IDL

LDL

HDL2

HDL3

Chylomicron

remnant

0.95

De

ns

ity (

g/m

L)

1.01

1.02

1.06

1.10

1.20

5 10 20 40 60 80 1000

Diameter (nm)Apolipoproteins (A-I, A-II, A-IV, A-V, B48, B100, C-I, C-II, C-III, C-IV)

• Assist in structural integrity and solubility

• Serve as co-factors in enzymatic reactions

• Act as ligands

Reduced APOC3 Loss-of-function Mutations

Show Reduced CHD Risk

The TG and HDL Working Group of the Exome Sequencing Project, NHLBI. New Eng J Med. 2014;371:22-31.

Loss-of-function

mutations reduced

TG levels by 39%

Odds ratio of CHD of subjects with any of 4 APOC3 loss-of-function mutations

among 110,970 participants (34,002 patients with CHD and 76,968 controls) in 14

studiesStudy Ancestry CHD Odds Ratio

WHI EA 0.39

WHI AA 0.00

FHS EA 0.00

MDC-CVA EA 1.70

ARIC EA 0.59

ARIC AA 2.40

IPM EA 0.74

IPM HA 0.51

IPM AA 0.62

ATVB+VHS EA 0.43

OHS EA 0.35

PROCARDIS EA 0.56

HUNT EA 0.86

GoDARTS CAD EA 0.00

EPIC CAD EA 1.00

FIA3 EA 0.00

German CAD EA 0.54

WTCCC EA 0.98

All 0.60

0 1 2 3 4 5

PROVE IT-

TIMI 22 Trialb

TG ≥150 mg/dL Predicts Higher CHDa Risk in

Statin Takers with LDL-C <70 mg/dL

CH

D E

ven

t R

ate

aft

er

30 D

ays

c(%

)

a. Death, MI, and recurrent ACS. b. ACS patients on atorvastatin 80 mg or pravastatin 40 mg. c. Adjusted for age, gender, low

HDL-C, smoking, hypertension (HTN), obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and

treatment. CHD=coronary heart disease; HR=hazard ratio; PROVE IT-TIMI=Pravastatin or Atorvastatin Evaluation and

Infection Therapy Thrombolysis In Myocardial Infarction. Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

(N=4162)

11.7%

16.5%

TG <150 mg/dL TG ≥150 mg/dL

LDL-C <70 mg/dL

HR: 0.72

P=0.017

HR: 0.84

P=0.192

Referent

LDL-C ≥70 mg/dL

TG ≥150 mg/dL

Event Rate=17.9%

0

10

15

20

5

Increasing TG Levels Increase Risk of

Pancreatitis

• Pancreatitis risk increases 4% for every 100 mg/dL increase in TG above 500 mg/dL*

0.0

0.5

1.0

1.5

2.0

2.5

Crude Incidence (cases/1000 pt-yr)

Triglycerides (mg/dL)

*After adjustment for covariates and removal of patients hospitalized for gallstones, chronic

pancreatitis, alcohol-related morbidities, renal failure, and other biliary disease.

Murphy MJ et al. JAMA Intern Med. 2013;173:162-4.

≤150(n=31,740)

150-499(n=31,887)

≥500(n=3642)

Group 1

Group 2

Group 3

How Should We Use Lipid

Measures, Including

Triglycerides, to Assess CV

Risk in Patients with

Dyslipidemia?

LDL-C Underestimates CVD Risk in HTG

Apo B

LDL=

130 mg/dL

Large LDL-C Small, dense LDL-C

CE

Otvos JD et al. Am J Cardiol. 2002;90:22i-29i.

Fasting Lipid Panel:

TC 198 mg/dL

LDL-C 130 mg/dL

TG 90 mg/dL

HDL-C 50 mg/dL

Non-HDL-C 148 mg/dL

Fasting Lipid Panel:

TC 210 mg/dL

LDL-C 130 mg/dL

TG 250 mg/dL

HDL-C 30 mg/dL

Non-HDL-C 180 mg/dL

↑Apo B

↑Non-HDL-C

↑LDL particles

↓HDL-C

NLA: Treatment Goals for Non-HDL-C,

LDL-C, and Apo B

Risk Category Treatment Goal (mg/dL)

Non-HDL-C LDL-C Apo B

Low <130 <100 <90

Moderate <130 <100 <90

High <130 <100 <90

Very High <100 <70 <80

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

2013 ACC/AHA Cholesterol Guideline* Was

Not Charged to Review HTG

• “Although elevations in LDL-C often occur

simultaneously with elevated triglyceride levels,

the Panel did not conduct a systematic review on

lifestyle and drug therapies for the treatment of

elevated triglyceride levels.”

• “Management of individuals with fasting

triglycerides >500 mg/dL has been addressed in

an AHA statementӠ

*Stone NJ et al. Circulation. 2014;129:S1-45. †Miller M et al. Circulation. 2011;123:2292-333.

NLA: Drug Therapy For TG Reduction

• A drug targeting TG reduction should be considered for

first-line therapy in those with TG ≥500 mg/dL

– TG-lowering drug therapies include fibric acids, high-dose long-

chain omega-3 fatty acids, and nicotinic acid

– A statin may be a reasonable first-line agent if the TG

concentration is ≥500 mg/dL, but <1000 mg/dL, if no history of

pancreatitis

• Combination therapy with a statin plus a second (or third)

agent may be considered for patients who have not

reached their treatment goals for atherogenic cholesterol

levels, particularly in those at high and very high risk

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

National Lipid Association (NLA): Targets

of Therapy – Triglycerides

• An elevated TG level is not a target of therapy per

se, except when very high (severe; ≥500 mg/dL)

• When TG levels are between 200–499 mg/dL, the

targets of therapy are non-HDL-C and LDL-C

• When the TG concentration is very high (≥500

mg/dL, and especially if ≥1000 mg/dL), reducing the

concentration to <500 mg/dL to prevent pancreatitis

becomes the primary goal of therapy

– Very similar to ATP III

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

Treating Underlying Factors of HTG

• Obtain Hx of diet (calories, fat, sugar, and ethanol

consumed) and physical activity

• Measure BMI (waist circumference), TSH, A1c, UA

• Prescribe less calories, sugar, ethanol, and fat. Prescribe

more physical activity

• Treat underlying co-morbidities

• Address TG-raising medications

Bays HE. In: Kwiterovich PO Jr, ed. The Johns Hopkins Textbook of Dyslipidemia.

1st ed. Lippincott Williams & Wilkins;2010:245-57.

Most Forms of HTG Are of Secondary Origin

HIV=human immunodeficiency virus.

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

Cause Clinically useful details

Positive energy balance Saturated fat, glycemic index content, alcohol

Carbohydrate intake Simple sugars (fructose, sucrose, etc.) & dietary fiber

Adiposopathy Especially visceral adiposity

Diabetes mellitus More so if poorly controlled

HypothyroidismOnly if not adequately controlled with thyroid replacement

therapy

Nephrotic syndrome

Medications

Antiretroviral regimens (for HIV)

Some phenothiazines and 2nd-generation antipsychotics

Nonselective beta-blockers

Thiazide diuretics

Oral estrogen, hormone Rx, tamoxifen

Glucocorticoids and isotretinoin

Recreational drugs Marijuana (ApoC-III)

Lifestyle and Diet Can Improve

Dyslipidemia

Diet / Lifestyle Change Lipid Profile Change

Weight loss (5–10%)TG (20%), LDL-C

(15%) & HDL-C (10%)

Diet

Fruits, vegetables & low-fat dairy;

Sugar

Total carb; Fat (to 33–50% of

calories)

LDL-C, HDL-C

Exercise

Brisk 30-min walk, 3x/wk

LDL-C

HDL-C (5–10%)

TG

Miller M et al. J Am Coll Cardiol. 2008;51:724-30. Sampson UK et al. Curr Atheroscler Rep. 2012;14:1-10.

TG

TG reduction values are not always corrected for baseline TG levels. Given that the greatest

reduction in TG levels occur in those with the highest TG levels at baseline, this may not be a

fair assessment of the TG-lowering effect of lipid-altering drugs in HTG patients.

AHA Scientific Statement: Treatment Effect

by Drug Class for Lowering TG Levels

Drug TG Reduction

Fibrates 30% – 50%

Omega-3 20% – 50%

Immediate-release niacin 20% – 50%

Extended-release niacin 10% – 30%

Statins 10% – 30%

Ezetimibe 5% – 10%

Miller M et al. Circulation. 2011;123:2292-333.

AHA Recommendations for OM-3

FA Intake

Kris-Etherton PM et al. Circulation. 2002;106:2747-57.

Population Recommendation

Patients without

documented CHD

• Eat variety of (preferably oily) fish at least 2X/wk

• Include oils and foods rich in -linolenic acid

(flaxseed, canola, soybean oils; flaxseeds; walnuts)

Patients with

documented CHD

• Consume ~1 g EPA+DHA daily, pref. from oily fish

• EPA+DHA supplements could be considered in

consultation with physician*

Patients needing

TG lowering

2–4 g EPA+DHA daily provided as capsules under

physician’s care

*Two recent RCTs showed no CVD benefit with this dose of EPA+DHA.ORIGIN Trial Investigators. N Engl J Med. 2012;367:309-18. Risk and Prevention Study Group. N Engl J Med. 2013;368:1800-8.

Statin + EPA: MARINE Trial Lipid Efficacy

TG >500 mg/dL

Me

dia

n P

lac

eb

o-a

dju

ste

d C

ha

ng

e (

%)

ITT Population

*P<0.0001. †P<0.001. ‡P<0.01. NS = P≥0.05. P-values reflect differences between EPA vs placebo.

ITT=intention to treat; Lp-PLA=lipoprotein-associated phospholipase A; MARINE=Multi-center, Placebo-controlled,

Randomized, Double-blind, 12-week Study with an Open-label Extension. Bays HE et al. Am J Cardiol. 2011;108:682-90.

-33.1

-17.7-16.3

-28.6

-3.6-2.3

-8.5

-13.6

-25.8

-35

-30

-25

-20

-15

-10

-5

0

* EPA 4 g/day

Non-

HDL-CTG TC

*

†

VLDL-C HDL-C

NS

LDL-C

NS

Apo B

‡

Lp-PLA2

†

VLDL-TG

‡

*

EPA+DHA and EPA-only: CVD Outcome

Studies

1. GISSI-Prevenzione Investigators. Lancet. 1999;354:447-55. 2. www.trialresultscenter.org/study4440-GISSI-P.htm. 3. ORIGIN Investigators. N Engl J

Med. 2012;367:309-18. 4. Risk and Prevention Study Group. N Eng J Med. 2013;368;1800-8. 5. Yokoyama M et al. Lancet. 2007;369:1090-8.

IFG=impaired fasting glucose; IGT=impaired glucose tolerance; NF=non-fatal; ORIGIN=Outcome Reduction with an Initial Glargine Intervention;

pbo=placebo; RRR=relative risk reduction.

GISSI-P1-2 ORIGIN3 Risk and Prevention4 JELIS5

OM-3 type

Dose

EPA+DHA

1 g/day

EPA+DHA

1 g/day

EPA+DHA

1 g/day

EPA1.8 g/day

Population Italian International Italian Japanese

N 11,324 12,536 12,513 18,645

Gender 85% male 65% male 61% male 31% male

Risk ProfileRecent MI (≤3 mos;

median 16 days)

High CV risk and IFG,

IGT, or T2DM

High CV risk, and

CAD but no MI

80% 1o prev; TC ≥6.5 mM; excl. MI ≤6 mos

prior

Follow-up 3.5 years 6.2 years (median) 5 years (median) 4.6 years (mean)

Statin Use Minimal53% in n-3 FA arm,

55% in pbo arm41%

All on statins(simvastatin or

pravastatin)

Primary End

Point

All-cause death, NF

MI, NF strokeDeath from CV causes

Death, non-fatal MI

and stroke

Major adverse cardiac event

ResultRRR 10% (P=0.048)

15% (P=0.023)

HR=0.98

P=0.72

HR=0.97

P=0.58

RRR 19% (no minimum TG level)

P=0.011

Baseline TG 162 mg/dL 158 mg/dL 150 mg/dL 153 mg/dL

JELIS: EPA Reduced Major Coronary Events*

in Hypercholesterolemic Patients on Statins

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

No. at Risk

Control

EPA

0 1 4 5 Years

9319 8931 8671 8433 8192 7958

9326 8929 8658 8389 8153 7924

Cu

mu

lati

ve I

ncid

en

ce o

f M

ajo

r

Co

ron

ary

Even

ts

(%)

4

P=0.011

Statin + EPA 1.8g/day

Statin only3

2

1

0

HR (95% CI): 0.81 (0.69–0.95)

↓

2 3

–19%

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.

*Pre-specified. MACE=major adverse CV event. Saito Y et al. Atherosclerosis. 2008;200:135-40.

JELIS: Larger Decrease in MACE in those with

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

HR and P-value

adjusted for age,

gender, smoking,

diabetes, and HTN

No. of patients

Control 475 444 432 414 400 392

EPA 482 455 443 427 413 403

0 1 2 3 4 5 Years

Cu

mu

lati

ve i

ncid

en

ce o

f m

ajo

r

co

ron

ary

eve

nts

(%

)

EPA 1.8 gm/day group

Control group–53%

HR: 0.47

95% CI: 0.23–0.98

P=0.043

5.0

4.0

3.0

2.0

1.0

0

Prescription vs Dietary Supplement OM-3

PrescriptionsDietary Supplements*

EPA EPA+DHA

FDA classification Drug Drug Food

FDA approval Yes Yes No

Ingredients EPAEPA

+ DHAVariable EPA + DHA (none pure EPA) +

other PUFAs and saturated FA

OM-3 per capsule 1 g 1 g Usually 0.2–0.4 g EPA; 0.1–0.3 g DHA

Capsules/day to

provide 4 g EPA4 8 Usually 10–20

Recommended dose 4 g/day 4 g/day

• General: Eat oily fish or 1 g/day

• Prior CHD: 1–2 g/day (>2 g/day directed

by HCP)

• For TG: 2–4 g/day directed by HCP

Purity/efficacy & safety

testedYes Yes Not required (usually not done)*

*Recent study found that 20% of the 30 top-selling OM-3 products contained levels of OM-3s that averaged

30% less than stated on their labels. http://well.blogs.nytimes.com/2014/01/22/whats-in-your-fish-oil-supplements/?_php=true&_type=blogs&_r=0. https://labdoor.com/rankings/fish-oil.

FA=fatty acid; HCP=health care provider OM-3=omega-3.

Summary

• HTG is an important public health burden – Optimal (NOT Treatment target !) TG level is <100 mg/dL

– Common in central obesity and T2DM

– Causal factor for ASCVD events; OFTEN indicates excess of atherogenic

apoB particles, abnormal lipoprotein trafficking and metabolic dysfunction (

Insulin resistance, T2DM, etc.)

• Guidelines and recommendations– Appropriate nutrition and physical activity in all

– Medical Rx in very high/severe ↑TG (>500 mg/dL) to help prevent

pancreatitis

– Medical Rx TG 200–500 mg/dL in high risk patients on statin: subgroup

analyses shown to help

• Recommended medical Rx– Statins (reduces apoB in high risk, unless statin-intolerant)

– Fenofibrate (subgroup analyses positive for T2DM)

– OM-3 (EPA-only, JELIS and subgroup analysis positive)

– Niacin (for severe HTG but not routine with statin for TG < 500)