1

Role of Triglycerides

2

Objectives

Explain the metabolism of triglycerides and the relationship between triglycerides and HDL-C

Discuss the role of triglycerides in the metabolic syndrome

Describe the relationship between serum triglycerides and CVD risk

HDL-C=high-density lipoprotein cholesterol; CVD=cardiovascular disease

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Role of Triglycerides

Properties and Metabolism of Triglycerides

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Properties of Triglycerides

Triglycerides are a vehicle for energy storage, primarily in adipose tissue

Triglycerides have both exogenous and endogenous sources

– The liver synthesizes triglycerides from free fatty acids (FFAs)

– The Western diet contains vast amounts of triglycerides that are absorbed into the body via the intestine

Triglycerides circulate primarily in very low-density lipoproteins (VLDLs) and chylomicrons

Sarwar N et al. Circulation. 2007;115:450–458; Castelli WP. Am Heart J. 1986;112:432–437.

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Triglyceride Metabolism

LPL=lipoprotein lipase; FFA=free fatty acid; HL=hepatic lipase; LDL-C=low-density lipoprotein cholesterol; VLDL=very low-density lipoprotein; IDL=intermediate density lipoprotein; apo E=apolipoprotein E; apo B=apolipoprotein Bfrom Mahley RW et al. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa; Saunders: 2003;1642–1705; Castelli WP. Am J Heart. 1986;112:432–437.

Liver

Intestine Dietary fat + cholesterol

ChylomicronsChylomicrons

remnants

Bile acids

VLDL IDL

apo E mediated

apo B mediated

apo E mediated

Adiposetissue

Peripheraltissue

(with LDL-C receptors)

LPLHL

LPLHL

LPL

LPLLDL-C LDL-C receptorsreceptors

Remnant Remnant receptorsreceptors

FFA

FFA

FFA

LDL-C

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The Relationship Between Triglycerides and HDL-C

HDL-C concentrations depend on the metabolism of triglyceride-rich lipoproteins.

A rise in chylomicrons and VLDL allows increased translocation of cholesterol esters from HDL-C particles, decreasing the measured HDL-C level.

Elevated triglyceride levels thus help drive reduced levels of HDL-C.

This inverse relationship between triglycerides and HDL-C complicates analysis of their contributions to CAD risk.

HDL-C=high-density lipoprotein cholesterol; VLDL=very low-density lipoprotein; CAD=coronary artery diseasePatsch JR et al. Arterioscler Thromb. 1992;12:1336–1345.

7

NCEP III Factors Contributing to Elevated Triglycerides

High Triglyceride Risk Factors

Obesity/overweight

Physical inactivity

Cigarette smoking

Excess alcohol intake

High carbohydrate diet

Type 2 diabetes, renal failure, underactive thyroid

Certain drugs

Genetic factors

Most often elevated in metabolic syndrome

NCEP III=National Cholesterol Education Program Adult Treatment Panel IIIExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497; De Backer G et al. Eur J Cardiovasc Prev Rehabil. 2003;10(suppl 1):S1–S78; Pejic RN et al. J Am Board Fam Med. 2006;19:310–316.

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The Metabolic Syndromea

Risk Factor Defining LevelAbdominal obesity (waist circumference)

MenWomen

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

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

MenWomen

<1.03 mmol/L (<40 mg/dL)<1.3 mmol/L (<50 mg/dL)

Blood pressure ≥130/85 mm Hg

Fasting glucose ≥6.1 mmol/L (≥110 mg/dL)

Clinical Identification of the Metabolic Syndrome

aPatients are diagnosed with the metabolic syndrome if they have 3 or more of these risk determinantsHDL-C=high-density lipoprotein cholesterolfrom Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497; Adapted from De Backer G et al. Eur J Cardiovasc Prev Rehabil. 2003;10(suppl 1):S1–S78.

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Triglycerides, Atherogenic Dyslipidemia, and the Metabolic Syndrome

Elevated serum triglycerides combined with low HDL-C is referred to as atherogenic dyslipidemia.

Atherogenic dyslipidemia often occurs with small, dense LDL-C particles and is also referred to as the “lipid triad.”

Clinically, atherogenic dyslipidemia is seen most often with the metabolic syndrome.

The metabolic syndrome is strongly associated with the development of type 2 diabetes and clinical CHD.

HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease Szapary PO et al. Am Heart J. 2004;148:211–221.

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Role of Triglycerides

Triglycerides and CVD Risk

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Triglyceride Levels as an Independent Risk Factor for CHD?

Study Results

PROCAM High triglyceride levels predict major coronary events independent of HDL-C

Copenhagen Male Study High triglyceride levels predict major coronary events independent of HDL-C

Lipid Research Clinics Follow-up Study

Coronary mortality related to triglyceride levels, but not independent of HDL-C and LDL-C

Helsinki Heart Study The effect of triglyceride levels on CHD is jointly influenced by LDL-C and HDL-C levels

COLTS “Normal” triglyceride levels (1.1–2.2 mmol/L [100–199 mg/dL]) predict new cardiovascular events independent of HDL-C

Framingham Heart Study Triglycerides were a CHD risk factor only when HDL-C was1.03 mmol/L (40 mg/dL)

PROCAM=Prospective Cardiovascular Münster Study; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; COLTS= Baltimore Coronary Observational Long-Term Study; CHD=coronary heart diseaseTo convert triglycerides from mg/dL to mmol/L, divide by 88.57 Assmann G et al. Am J Cardiol. 1996;77:1179–1184; Jeppesen J et al. Circulation. 1998;97:1029–1036; Criqui MH et al. N Engl J Med. 1993;328:1220–1225; Manninen V et al. Circulation. 1992;85:37–45; Miller M et al. J Am Coll Cardiol. 1998;31:1252–1257; Castelli WP. Am Heart J. 1986;112:432–437.

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High Triglyceride Levels andCAD Risk in the Framingham Heart Study

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0.6 1.1 1.7 2.2 2.8 3.4 4 4.5

Triglyceride Level, mmol/L

Rel

ativ

e R

isk

of

CA

D

Men Women

N=5127 people aged 30–62 yearsCAD=coronary artery disease Miller M. Am J Cardiol. 2000;86(suppl):23L–27L; Castelli WP. Can J Cardiol. 1988;4:5A–10A.

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High Triglycerides and CHD Risk in Patients With Diabetes

10

40

30

20

0mmol/L <1.51 1.51–2.60 >2.60

Total Triglycerides

P<0.001

CHD mortality All CHD events

7-Y

ear

Inci

den

ce o

f C

HD

in T

ype

2 D

iab

etes

, %

N=1059CHD=coronary heart diseasefrom Lehto S et al. Diabetes. 1997;46:1354–1359.

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Triglycerides and CHD Risk: Meta-Analysisin Western Populations

CHD=coronary heart disease; CI=confidence interval; EPIC=European Prospective Investigation of Cancer; APCSC=Asia Pacific Cohort Studies Collaborationfrom Sarwar N et al. Circulation. 2007;115:450–458.

This meta-analysis involves >260,000 participants and includes information from a total of >10,000 CHD cases

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Cumulative Incidence of MI and IHD by Levels of Nonfasting Triglyceridesa

MI in Women

0

20

40

60

80

100

45 55 65 75 85 95

MI=myocardial infarction; IHD=ischemic heart disease. from Nordestgaard BG et al. JAMA. 2007;298:299–308.

Age, y

Cu

mu

lati

ve

In

cid

en

ce

, %

MI in Men

0

20

40

60

80

100

45 55 65 75 85 95

IHD in Women

0

20

40

60

80

100

45 55 65 75 85 95

IHD in Men

0

20

40

60

80

100

45 55 65 75 85 95

Age, y

Cu

mu

lati

ve

In

cid

en

ce

, %

a Prospective cohort study of 13,981 individuals in Copenhagen followed from 1976 to 2004

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Association of Fasting vs Nonfasting Triglyceride Levels With Future Cardiovascular Eventsa

a Prospective study of 26,509 initially healthy women

HR and 95% CI adjusted for age, blood pressure, smoking, hormone use, total cholesterol level, diabetes mellitus, BMI, and high-sensitivity C-reactive protein level, using triglyceride levels <1.7 mmol/L (<150 mg/dL), and HDL-C levels ≥1.3 mmol/L (≥50 mg/dL) as the reference group

HDL-C=high-density lipoprotein cholesterol; HR=hazard ratio; CI=confidence interval; BMI=body mass indexfrom Bansal S et al. JAMA. 2007;298:309–316.

0.5 1.0 10

HDL-C ≥1.3 mmol/L

Triglycerides <1.7 mmol/L

Triglycerides ≥1.7 mmol/L

HDL-C <1.3 mmol/L

Triglycerides <1.7 mmol/L

Triglycerides ≥1.7 mmol/L

Fasting Nonfasting

Fully Adjusted HR (95% CI)

Fully Adjusted HR (95% CI)

0.5 1.0 10

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Summary

The metabolism of triglyceride-rich chylomicrons and VLDL lowers HDL-C, creating an inverse relationship between triglycerides and HDL-C.

Low HDL-C and high triglycerides commonly occur together in the metabolic syndrome.

Many studies have found triglyceride levels to be positively correlated with coronary events. The significance of this association may often be weakened by the influence of HDL‑C.

Nonfasting triglycerides may be an independent predictor of CVD and fasting triglycerides are not.

VLDL=very low-density lipoprotein; HDL-C= high-density lipoprotein cholesterol; CVD=cardiovascular disease

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Bibliography

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Role of Triglycerides

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