Bart Staels

Bart Staels

INSERM UR545; Institut Pasteur de Lille; Université Lille Nord de France

Lille, France

Triglycerides as a Risk Factor for Cardiovascular Disease

Triglycerides and CVD

• Epidemiological studies

• Intervention studies

• Pathophysiology of atherogenic dyslipidemia

• Niacin• Fibrates

• Genes and genome-wide association studies

PROCAM Study

Are triglycerides an independent risk factor?

Mls

/ 1

00

0/

10

ye

ars

TriglyceridesTertiles(mg/dL)

LDL-Cholesterol tertiles(mg/dL)

0

50

100

150

200

<132 132-162 >162

< 104

< 104-165

>165

Triglyceride Level Is An Independent CVD Risk Factor

Recent Meta-analysis of 29 Studies

Sarwar N, et al. Circulation. 2007;115:450–458*Individuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most)

CHD Risk Ratio* (95% CI)

1.72 (1.56-1.90)

21

Duration of follow-up≥10 years 5902

<10 years 4256

SexMale 7728

Female 1994

Fasting statusFasting 7484Nonfasting 2674

Adjusted for HDL-CYes 4469No 5689

N=262 525

Groups CHD Cases

Overall CHD Risk Ratio*Decreased

RiskIncreased

Risk

(440 mg/dL)

(<90)

Age (yr)0 50 60 70 80 90 100

Cu

mu

lativ

e in

cid

enc

e (

%)

0

20

40

60

80

100

5

12 - 3

Triglycerides(mmol/L)

Myocardial infarction in CCHSWomen

N=7600Follow-up: 28 years

Nordestgaard et al. JAMA 2007

PROVE IT-TIMI-22 post-hoc analysis: on-treatment elevatedtriglycerides (>200 mg/dL) significantly increased the risk of death, MI or ACSin patients who achieved LDL cholesterol levels <70 mg/dl on statin therapy Miller M et al J Am Coll Cardiol 2008;51:724

0

5

10

15

20

25

30-d

ay r

isk

of d

eath

, MI

Or

recu

rren

t AC

S (

%)

>200(n=603)

<200(n=2,796)

on-treatment TG (mg/dL)

20.3

13.5RR0.64 (0.53-0.78)P=0.001

High triglycerides contribute to the residual risk after statin treatment







Reduction in plasma triglycerides (start >1.5 mmol/L)R

edu

ctio

n i

n i

sch

emic

hea

rt d

isea

se 0%

-10%

-30%

-20%

-40%

0% -10%

-20%

-30% -40% -50%

Helsinki IV

VA-HIT

Helsinki IIBBIP

Post hoc subanalysis of double-blind trials

Carlson & Rosenhamer

Randomized trial unblinded

FIELD

Nordestgaard 2010







Statin+niacin vs statin+ezetimibe on lipids – ARBITER 6

Statin+niacin vs statin+ezetimibe on lipids – ARBITER 6

Taylor et al, NEJM, 361:2113-2122, 2009

Statin + niacin is more effective at reducing CIMT than statin plus ezetimibe - ARBITER 6

Statin + niacin is more effective at reducing CIMT than statin plus ezetimibe - ARBITER 6

Major CVD events were lower in the niacin than in the ezetimibe groupMajor CVD events were lower in the niacin than in the ezetimibe group (1% vs. 5%, P=0.04)(1% vs. 5%, P=0.04)

Taylor et al, NEJM, 361:2113-2122, 2009







mitochondrial FA-oxidation

TG secretion

Fibrates

PPAR

Fibrates control triglyceride andremnant-lipoprotein metabolism

Liver

Plasma TG

apo A-Vproduction

apo C-IIIproduction

TG clearance

sdLDL

PControl

<.024.1% 34%2.7%4081 HHS Primary Prevention

Rel.RRDrugNTrial

Major CVD Event Rate

.2615.0% 9.4%13.6%3090 BIPSecondary Prevention

.00621.7% 22%17.3%2531 VA-HIT

Diabetic dyslipidemia or Metabolic Syndrome subgroupsvs overall population

FIELD .1611.7% 11%10.4%9795

Mixed (Primary+Secondary)

Fibrates decrease CV risk in patients with metabolic syndrome and diabetic dyslipidemia

0.00717.8% 26%13.5%2014MS Dyslipidemia

.03 18.4% 25%14.1%1470MS

<.00513.0% 71%3.9%292MS dyslipidemia

.00436.5% 32%24.5% 769Diabetics

Scott R et al Diabetes Care 2009; 32:493-498

*HDL-c: <40 mg/dL(men) and <50 mg/dL (women)

Allpatients

5-ye

ar to

tal C

VD

eve

nt r

ate

(%)

0

5

10

15

20

13.912.5

Hazard ratio:(95%) Cl:P-value:

0.89(0.80-0.99)

P=0.035

Low HDL-C

15.1

13.0

0.85(0.74-0.97)

P=0.02

TG>150mg/dL

15.4

13.6

0.88(0.75-1.01)

P=0.07

Low HDL-C +TG>200 mg/dL

17.8

13.5

0.74(0.59-0.92)

P=0.01

Highest therapeutical benefit of fenofibrate in patients with elevated TG and low HDL cholesterol

(FIELD study)







Nature Genetics 2008;40,161

GWAS Identify Genes Involved in Triglyceride MetabolismAssociated with CAD Risk

Genes in plasma triglyceride metabolism:LPL, ApoCIII, ApoAI-CIII-AIV, Apo AV, ANGPTL3

Genes in hepatic triglyceride synthesis:GCKR, MLXIPL

Other:TRIB1

ApoCIII Underlies the Abnormal Metabolism of VLDL and LDL in HyperTG and with a High-Carbohydrate Diet

VLDL CIII+Large TG-rich nascent particle

LDL CIII+TG-rich remnant

Dense LDL CIII-Dense LDL CIII-Major LDL TypeMajor LDL Type

TG

TG

Zheng C, Sacks F. JLR 2007;48:1190

++

++

Slow clearance

-

-

++

-CIII

Zheng C. Am J Clin Nutr 2008;88:272

Caron S & Staels B, Circ Res 2008

ApoCIII : a link between hypertriglyceridemiaand vascular dysfunction?

Triglyceride-richLipoproteins (Lp)

TG-richLipo-

proteins

apoCIII

TriglycerideMetabolism

VLDL production

TG metabolism

TG-rich Lp/VLDLclearance

TG-rich Lp/VLDLuptake

Blood

Adhesion moleculeexpression (VCAM-1,ICAM-1)

Endothelial cells

NO production

vasoconstriction

Endothelial dysfunction –Inflammation

1-integrin expression

Monocytes

Monocyte adhesion

on ECs

TLR2 activation

Micro- & Macrovascular diseases (CVD)

CARE

Triglycerides and Apo CIII in VLDL and LDL to Predict CHD

Univariate

RR

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Q1 Q2 Q3 Q4 Q5

Triglycerides

p=0.03

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Q1 Q2 Q3 Q4 Q5

Apo CIII in VLDL+ LDL

Triglycerides (NS)

p=0.04

Multivariate

RR

Sacks, Alaupovic, et al. Circulation 2000;102:1886

ApoCIII Genetic Variant Correlates with Triglyceridesand Coronary Artery Calcification

Pollin T. et al. Science 2008;322,1702

0

1000

2000

3000

4000

5000

6000

7000

8000

29 39 49 59 69 79 89 99

Age (years)

Co

ron

ary

Art

ery

Ca

lcif

ica

tio

n

RR

RX







The Metabolic Syndrome:a Major Health Problem

Control of plasma triglyceridemetabolism

Plasma TG

apo A-V/apo CIIIproduction

LPLproduction

Lipolytic activity/TG clearance

sdLDL

hepaticlipogenesis

mitochondrial FA-oxidation

TG secretion

Insulin Resistance and Dyslipidemia

TGTG Apo BApo B

VLDLVLDL (large)(large)

IA Fat CellsIA Fat Cells

InsulinInsulin

IRIR XX

LiverLiver

FFAFFACytokineCytokine

ss

LDLLDL

(CETP)(CETP) TGTGCECE

(( HL) HL) Small DenseSmall Dense

LDLLDLLDL

CECE

TGTG

(CETP)(CETP) HDLHDL22

(( HL) HL)

KidneyKidney

Apo A-1Apo A-1

HDL3

FFA: Free fatty acidsCETP: Cholesteryl ester transfer proteinHL: Hepatic lipase

Liver

Adipocytes

NEFA

TG

HSL

Lipolysis

HYPERGLYCEMIAHYPERINSULINEMIA FA TG

TG

TGLipogenesis EsterificationTG

TG

TG

CM

Gut

-oxidation

VLDL

Hepatic lipid accumulation is related to insulin resistanceand associated with increased VLDL1 production







• Conclusions

Elevated TG is marker for atherogenic remnant lipoproteins

Although unclear whether TG is a direct cause of CAD, it is a marker for:

• Increased small-dense LDL particles

• Decreased HDL2 cholesterol

• Increased remnant lipoproteins

Causal factor with variation

Glucose

Longterm monitoring

HbA1c

TG Remnants HDL

Nordestgaard et al. Current Drug Targets, 2009, 10, 328-335

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Bart Staels