Hypertriglyceridemia and CVD Risk: Significance, Relationship to Other Lipid Biomarkers, and Assessment

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

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

Disclosures • Consulting Fees: Aegerion, Amarin, Novartis • Fees for Non-CME/CE Services: Amarin, AstraZeneca,

Kowa, Sanofi/Genzyme

Overall Prevalence of HTG Based on Cut Points by Age, Sex, and Ethnicity in NHANES 1999–2008

aData are given as percentage of participants. bExcludes pregnant women. Miller M et al. Circulation. 2011;123:2292-333. Does not include those whose race/ethnicity was “other”. c Includes fenofibrate, gemfibrozil, niacin, statin, or ezetimibe. Ford ES et al. Arch Intern Med. 2009;169:572-8. dUS Census Age 20 and above, July 1, 2010, was 226,113,653. HTG=hypertriglyceridemia; NHANES=National Health and Nutrition Examination Survey; TG=triglyceride(s); yrs=years.

TG Cut Points, mg/dLa Demographic ≥150 ≥200 ≥500 Overall (age ≥20 yrs) 31 16 1.1 Men 35 20 1.8 Womenb 27 13 0.5 Mexican American 35 20 1.4 Non-Hispanic, black 16 8 0.4 Non-Hispanic, white 33 18 1.1 Use of TG-lowering medication 18

70 million persons, or ~1/3 of US adults, have elevated TG (≥150 md/dL)d

TG Revisions between 1984 and 2001

2011 AHA Statement classified TG <100 mg/dL as “OPTIMAL” (SD LDL becomes much more prevalent with TG >100 mg/dL)

*All measurements in mg/dL. AHA=American Heart Association; ATP=Adult Treatment Panel; LDL=lipoprotein cholesterol; NCEP=National Cholesterol Education Program; NIH=National Institutes of Health; SD=small dense. Miller M et al. Circulation. 2011;123:2292-33.

AHA Scientific Statement on TG Classification

TG Designation

1984 NIH Consensus Panel

1993 NCEP ATP II

2001 NCEP ATP III

Desirable* <250 <200 <150 Borderline High* 250–499 200–399 150–199

High* 500–999 400–999 200–499

Very High* >1000 >1000 >500

Primary Causes of HTG

Relatively common • Familial combined hyperlipidemia (FCHL)

– Variable phenotype (↑TG alone, or ↑TC alone, or both increased) – Associated with ↑↑CVD and ↑central obesity – Multiple genetic associations of unclear causal significance – “Hyper-Apo B”

• Familial HTG (FHTG) – ↑TG alone (not TC) – Associated with ↑CVD if ↑central obesity / MetS – Largely due to ↑hepatic VLDL production – Apo B is usually normal

Rare • LPL deficiency • Apo C-II deficiency • Familial dysbetalipoproteinemia (Type III) • GPIHBP1 deficiency

Note: FCHL and FHTG may NOT be distinct entities

Apo=apolipoprotein; CV=cardiovascular; CVD=CV disease; GPIHBPI=glycophosphatidylinositol-anchored high-density lipoprotein (HDL)-binding protein; LPL=lipoprotein lipase; MetS=metabolic syndrome; TC=total cholesterol; VLDL=very-low-density lipoprotein. Bays HE. In: Kwiterovich PO Jr, ed. The Johns Hopkins Textbook of Dyslipidemia. 1st ed. Lippincott Williams & Wilkins;2010:245-57.

Secondary Causes of HTG

Adapted from 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 or ↑Glycemic index content

↑Carbohydrate intake ↑Fructose (& other sugars?) with ↓Dietary fiber

Adiposopathy (especially ↑visceral adiposity)

Impaired adipogenesis, adipocyte hypertrophy, & adipose tissue dysfunction

Diabetes mellitus Especially if poorly controlled

Hypothyroidism If untreated or uncontrolled

Nephrotic syndrome

Medications

Antiretroviral regimens (for HIV) Some phenothiazines and 2nd-generation antipsychotics Nonselective beta-blockers Thiazide diuretics Oral estrogen, tamoxifen Bile acid sequestrants Glucocorticoids and Isotretinoin

Recreational drugs Alcohol (esp. with fatty liver) and Marijuana

Note: Common causes are in yellow

Association Between BMI and HTG NHANES 1999–2004

TG Concentration (mg/dL)

BMI (kg/m2)

<150 (n=3250)

<200 (n=4057)

≥150 (n=1744)

≥200 (n=937)

<25 42.7 39.0 20.1 17.5

25 to <30 31.6 33.3 39.9 39.6

≥30 25.6 27.7 39.9 42.9

BMI=body mass index. Miller M et al. Circulation. 2011;123:2292-333.

Percent of participants within a TG category as a function of BMI status

~2.5 greater prevalence

Global Cardiometabolic Risk*

*working definition Gelfand EV, Cannon CP. J Am Coll Cardiol. 2006;47:1919-26. Vasudevan AR, Garber AJ. Minerva Endocrinol. 2005;30:101-19.

Risk Factor Defining Level Abdominal obesity Men Women

Waist circumference >102 cm (>40 in) >88 cm (>35 in)

Triglycerides ≥150 mg/dL (1.7 mmol/L) HDL-C Men Women

<40 mg/dL (1.04 mmol/L) <50 mg/dL (1.30 mmol/L)

Blood pressure ≥130 / ≥85 mm Hg Fasting glucose ≥100 mg/dL (5.6 mmol/L)

Metabolic Syndrome: The NCEP ATP III Definition*

*2001, updated 2005 (Grundy SM et al. Circulation. 2005;112:2735-52). HDL-C=HDL cholesterol. NCEP ATP III. Circulation. 2002;106:3143-421.

To make a diagnosis of MetS, a patient must present with 3 or more of the following 5 risk factors:

MetS-NCEP +

EWET -

CV event rate P<0.001

-2 0 2 4 6 8 10 0.7

0.8

0.9

1.0

1.1

Follow-up Time (yrs)

Cum

ulat

ive

Surv

ival

Cum

ulat

ive

Surv

ival

0.7

0.8

0.9

1.0

1.1

-2 0 2 4 6 8 10

P<0.001

MetS-NCEP -

EWET +

CV event rate

Kaplan-Meier curves indicating CV event rates in women with EWET (n=88) or without EWET (n=469) or with MetS (n=100) or without MetS (n=433) as per 2001 NCEP.

Follow-up Time (yrs)

Enlarged Waist Combined with Elevated TG (EWET) May Predict CVD as Well as MetS in Menopausal Women

EWET=Waist ≥88 cm and TG ≥128 mg/dL. Tankó LB et al. Circulation. 2005;111:1883-90.

Relationship of MetS and CVD Outcomes Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial

25

20

15

10

5

0 0 4 8 12 16

Weeks Since Randomization

Adjusted HR (95% CI) 1.49 (1.24–1.79)

Cum

ulat

ive

Haz

ard

(%)

Metabolic Syndrome No Metabolic Syndrome

Primary endpoint: Composite of death, nonfatal myocardial infarction (MI), resuscitated cardiac arrest, and recurrent ischemia with evidence requiring hospitalization. CI=confidence interval; HR=hazard ratio. Schwartz GG et al. Diabetes Care. 2005;28:2508-13.

HTG and Event-free Survival in Patients Undergoing PCI

TG <150 mg/dL TG ≥150 mg/dL

100

90

80

70

60

50

0 5 10 15 20

P=0.063

Numbers at risk TG <150 mg/dL 450 375 331 56 TG ≥150 mg/dL 298 229 196 58

Cum

ulat

ive

Even

t-fre

e Su

rviv

al (%

)

Years after percutaneous coronary intervention (PCI)

Kasai T et al. Circ J. 2006;70:1531-7.

TG Levels and CHD Risk: Meta-analysis of 29 Studies

*Individuals in top vs bottom third of usual log-TG values, adjusted for at least age, sex, smoking status, lipid concentrations, and (in most studies) blood pressure (BP). CHD=coronary heart disease. Sarwar N et al. Circulation. 2007;115:450-8.

Groups CHD Cases Duration of Follow-up ≥10 years 5902 <10 years 4256

Gender Male 7728 Female 1994 Fasting Status Fasting 7484 Nonfasting 2674

Adjusted for HDL-C Yes 4469 No 5689

Decreased Risk

CHD Risk Ratio* (95% CI)

1.72 (95% CI, 1.56–1.90)

2 1 Increased Risk

N=262,525

Top Tertile of TG defined as >181

mg/dL

Lowest Tertile of TG defined as <120 mg/dL

Overall CHD Risk Ratio*

Residual CVD Risk in Major Statin Trials

4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-7. 6 Downs JR et al. JAMA. 1998;279:1615-22.

14S Group. Lancet. 1994;344:1383-9. 2LIPID Study Group. N Engl J Med. 1998;339:1349-57. 3Sacks FM et al. N Engl J Med. 1996;335:1001-9.

0

10

20

30

40

4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/ TexCAPS6

N 4444 4159 20,536 6595 6605 9014 Secondary High Risk Primary

Patie

nts

Expe

rienc

ing

M

ajor

CH

D E

vent

s, %

Placebo Statin

19.4

12.3 10.2 8.7

5.5 6.8

28.0

15.9 13.2 11.8

7.9 10.9

CHD events occur in patients treated with statins

4S=Scandinavian Simvastatin Survival Study; AFCAPS= Air Force Coronary Atherosclerosis Prevention Study (CAPS); CARE=Cholesterol and Recurrent Events; HPS=Heart Protection Study; LIPID= Long-term intervention with pravastatin in ischemic disease; TexCAPS=Texas CAPS; WOSCOPS=West of Scotland Coronary Prevention Study.

Can HTG Cause Atherosclerosis?

Con • HTG → CVD weaker than LDL-C, partly HDL-C dependent • Severe HTG from ↑chylomicrons not related to ↑CVD • TG accumulation not seen in atherosclerotic plaque • TG-lowering drugs not completely proven to ↓CVD Pro • TG-rich lipoproteins are atherogenic (esp. cholesterol-rich

remnants) • TG lipolysis by LPL → pro-inflammatory FFA (uptake by CD36 &

FA binding proteins to nucleus) • HTG causes atherogenic changes in LDL and HDL • TG-lowering drugs ↓CVD in HTG / low HDL-C patients • TG ~100-800 mg/dL is OFTEN associated with hyper-Apo B (ie,

pro-atherogenic state) FA= fatty acid; FFA=free FA; LDL-C=LDL cholesterol. Miller M et al. Circulation. 2011;123:2292-333.

Baseline TG Levels Predict 5-Year Risk in Statin-Treated Patients

18.320.3

23.2 24.7

0

10

20

30

HPS CARE / LIPID

Low TG + statin High TG + statin

CVD

Eve

nt R

ate

(%)

1HPS Collaborative Group. Lancet. 2002;360:7-22. 2Sacks FM et al. Circulation. 2000;102:1893-900.

1 2

↑26.8% ↑21.7%

TG <150 mg/dL Associated with Lower Risk of CHD Eventsa Independent of LDL-C Level

Achieving both low LDL-C and low TG (<150 mg/dL) may be important therapeutic strategies in patients after ACS

aDeath, MI, and recurrent acute coronary syndromes (ACS). bACS patients on atorvastatin 80 mg or pravastatin 40 mg. cAdjusted for age, gender, low HDL-C, smoking, hypertension (HTN), obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment. 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.

PROVE IT-TIMI 22 Trialb

CH

D E

vent

a Rat

e af

ter

30 D

aysc

(%)

N=4162

0

5

10

15

20

11.7%

16.5% 15.0%

17.9%

TG <150 TG ≥150

LDL-C ≥70 LDL-C <70

HR: 0.72 P=0.017

HR: 0.85 P=0.180

HR: 0.84 P=0.192

Referent

Lipid values in mg/dL

HDL

LDL

IDL

VLDL A

ther

ogen

ic L

ipop

rote

ins

Non

-HD

L-C

(lip

id);

Apo

B (p

rote

in)

Intermediate-density lipoprotein – Formed from VLDL with loss of TG – TG ≈ CE – Also known as a VLDL remnant

Low-density lipoprotein – Formed from IDL with loss of TG – CE >> TG – Main plasma cholesterol carrier

High-density lipoprotein – Removes cholesterol from peripheral tissues – Other anti-athero effects

Lp(a) Lipoprotein (a)

– Formed from LDL plus Apo (a) – Very atherogenic/pro-oxidative

Very-low-density lipoprotein – Made in the liver – TG >> CE – Takes lipids from the liver to periphery

Non-HDL-C Includes All Atherogenic Lipoprotein Classes

Non-HDL-C

Non-HDL-C = TC – HDL-C

CE=cholesterol ester.

Elevated TG Associated with ↑SD LDL-P, ↑Non-HDL-C, ↓HDL-C

Apo B

LDL= 130 mg/dL

Fewer Particles More Particles

CE

More Apo B

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

Fatty liver

Three Atherogenic Consequences of HTG

TG

CE

CETP HDL

Hepatic Lipase

Kidney

Rapid Loss of Apo A-I

HDL & Apo A-I

SD HDL

3

TG

VLDL-C 1

CE

TG CETP

SD LDL

LDL size Apo B & LDL-P

Hepatic Lipase LDL

2

VLDL

FFA / TG and Fructose

(glucose)

Central Adiposity

FFA / TG

↑VLDL Synthesis

Fatty liver & ↑VLDL synthesis are key to ↑TG and consequences

“Atherogenic Dyslipidemia” ↑TG/VLDL-C SD LDL/↑LDL-P ↓HDL-C & Apo A-I

1 2 3

CETP=CE transfer protein; LDL-P=LDL particle(s); VLDL-C=VLDL cholesterol.

Rationale for Non-HDL-C Assessment

1NCEP ATP III. Circulation. 2002;106:3143-421. 3Brunzell JD et al. J Am Coll Cardiol. 2008;51:1512-24. 2Miller M et al. Circulation. 2011;123:2292-333. 4Mora S. Circulation. 2009; 119:2396-404.

• In the presence of HTG (>200 mg/dL), non-HDL-C assesses atherogenic particles better than LDL-C1

• Unlike calculated LDL-C, non-HDL-C can be accurately measured in nonfasting patients2,3

• Non-HDL-C is highly correlated with total Apo B1

– Serum total Apo B has been shown to have a strong predictive power for severity of coronary atherosclerosis and CHD events1

• Non-HDL-C is the difference between 2 values in the standard lipid panel (ie, TC – HDL-C) and therefore incurs no additional cost1,4

The Framingham Study: Non-HDL-C is Superior to LDL-C in Predicting CHD Risk

0

0.5

1

1.5

2

2.5

LDL-C (mg/dL) Non-HDL-C (mg/dL)

Rel

ativ

e C

HD

Ris

k

<130 130–159 ≥160

≥190 160–189

<160

N=5794 • In HTG, at a given non-HDL-C level, little / no association between LDL-C and CHD

• In contrast, non-HDL-C predicts CHD at all LDL-C levels

• Non-HDL-C is a much stronger CHD risk predictor than LDL-C

Note also that non-HDL-C is: • Included (free) in lipid panel •Accurate non-fasting •Accurate in HTG pts •Already in the guidelines •Close approximation to Apo B and LDL-P

Reference group

Liu J et al. Am J Cardiol. 2006;98:1363-8.

Targets for Therapy after LDL-C Goal in Patients with TG ≥200 mg/dL

RF=risk factor. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-97.

Patient Category LDL-C target (mg/dL)

Non-HDL-C target (mg/dL)

No CHD, <2 RFs <160 <190

No CHD, 2+ RFs <130 <160

CHD or CHD risk equivalent <100 <130

43 50

56

67 75

83

0

25

50

75

100

Hypertriglyceridemic Patientsa Not Achieving Combined LDL-C and Non-HDL-C Goals

Pat

ient

s N

ot A

chie

ving

Goa

l, %

CHD, n=320

Not achieving LDL-C goal Not achieving LDL-C and Non-HDL-C goals

aTGs ≥200 mg/dL (2.25 mmol/L)

Diabetes (no CHD) n=308

Other Risk Equivalents (no CHD)

n=100

NEPTUNE II: Patients With CHD and CHD Risk Equivalents

NEPTUNE=NCEP Evaluation Project Utilizing Novel E-Technology. Davidson MH et al. Am J Cardiol. 2005;96:556-63.

49-yo woman with T2DM controlled on metformin and statin • Exam: BMI=29 kg/m2, BP=129/82 mm Hg, Waist=41” • Meds: Metformin 1000 mg bid, ASA 81 mg/d, atorvastatin

40 mg/d • Labs A1c 6.5% TC 177 mg/dL TG 550 mg/dL LDL-C 75 mg/dL HDL-C 38 mg/dL Non-HDL-C 139 mg/dL

A1c=glycated hemoglobin; ASA=aspirin; T2DM=type 2 diabetes mellitus.

Risk Assessment

This patient has a high residual risk. Risk status established, set goals for therapy.

Risk factor Patient Gender: Male No

Age: >45 years Yes: 49 years

Previous MI No

T2DM Yes: T2DM = CHD risk equivalent

MetS: 3 of 5 RFs 1. Waist >35” 2. T2DM 3. HDL-C <50 mg/dL 4. TG ≥150 mg/dL 5. HTN

Yes: MetS 1. Yes: 41” 2. Yes 3. Yes: 38 mg/dL 4. Yes: 550 mg/dL 5. No: BP 129/82 mm Hg

ATP III Treatment Recommendations for Elevated TGs

TG (mg/dL)

ATP III Classification

Primary Target of Therapy Treatment Recommendations

150–199 Borderline high LDL-C goal ↓Weight and ↑Physical activity

200–499 High LDL-C goal

↓Weight and ↑Physical activity Consider non-HDL-C goal: ↓LDL-C with statin or ↓VLDL-C with niacin or fibrate ↓Sugar/carbs*

≥500 Very high

↓TG to prevent acute pancreatitis

Very low fat diet (fat ≤15% total calories) ↓Weight and ↑Physical activity Add niacin or fibrates (+OM-3 as per FDA indication*)

*Not in ATP III statement. FDA=US Food and Drug Administration; OM=omega. NCEP ATP III. Circulation 2002;106:3143-421.

Conclusions

• Despite effective LDL-C-lowering statin therapy, significant atherogenic CVD risk remains

• TG assessment is important to evaluate for CV risk

• Elevated TG levels are associated with increased CVD risk and contribute to atherogenic dyslipidemia

• Non-HDL-C is highly correlated with Apo B and LDL-P, and may be a better and more easily obtainable marker for atherogenic CV risk than LDL-C