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/ 1000/ 10 years Triglycerides Tertiles (mg/dL) LDL-Cholesterol tertiles (mg/dL) < >162 < 104 < >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 ( ) 21 Duration of follow-up ≥10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL-C Yes 4469 No 5689 N= GroupsCHD Cases Overall CHD Risk Ratio* Decreased Risk Increased Risk

(  440 mg/dL) (<90) Age (yr) Cumulative incidence (%)  5  Triglycerides (mmol/L) Myocardial infarction in CCHS Women N=7600 Follow-up: 28 years Nordestgaard et al. JAMA 2007

PROVE IT-TIMI-22 post-hoc analysis: on-treatment elevated triglycerides (>200 mg/dL) significantly increased the risk of death, MI or ACS in patients who achieved LDL cholesterol levels <70 mg/dl on statin therapy Miller M et al J Am Coll Cardiol 2008;51: day risk of death, MI Or recurrent ACS (%) >200 (n=603) <200 (n=2,796) on-treatment TG (mg/dL) RR0.64 ( ) P=0.001 High triglycerides contribute to the residual risk after statin treatment

Triglycerides and CVD Epidemiological studies Intervention studies Pathophysiology of atherogenic dyslipidemia Niacin Fibrates Genes and genome-wide association studies

Reduction in plasma triglycerides (start >1.5 mmol/L) Reduction in ischemic heart disease 0% -10% -30% -20% -40% 0%-10% -20% -30%-40%-50% Helsinki IV VA-HIT Helsinki IIB BIP Post hoc subanalysis of double-blind trials Carlson & Rosenhamer Randomized trial unblinded FIELD Nordestgaard 2010

Triglycerides and CVD Epidemiological studies Intervention studies Pathophysiology of atherogenic dyslipidemia Niacin Fibrates Genes and genome-wide association studies

Statin+niacin vs statin+ezetimibe on lipids – ARBITER 6 Taylor et al, NEJM, 361: , 2009

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 group (1% vs. 5%, P=0.04) (1% vs. 5%, P=0.04) Taylor et al, NEJM, 361: , 2009

Triglycerides and CVD Epidemiological studies Intervention studies Pathophysiology of atherogenic dyslipidemia Niacin Fibrates Genes and genome-wide association studies

mitochondrial FA  -oxidation TG secretion Fibrates PPAR  Fibrates control triglyceride and remnant-lipoprotein metabolism Liver Plasma TG apo A-V production apo C-III production TG clearance sdLDL

PControl <.024.1%34%2.7%4081 HHS Primary Prevention Rel. RRDrugNTrial Major CVD Event Rate %9.4%13.6%3090 BIP Secondary Prevention %22%17.3%2531 VA-HIT Diabetic dyslipidemia or Metabolic Syndrome subgroups vs overall population FIELD % 11%10.4%9795 Mixed (Primary+Secondary) Fibrates decrease CV risk in patients with metabolic syndrome and diabetic dyslipidemia % 26%13.5% 2014MS Dyslipidemia %25%14.1%1470MS < %71%3.9%292MS dyslipidemia % 32%24.5% 769 Diabetics

Scott R et al Diabetes Care 2009; 32: *HDL-c: <40 mg/dL(men) and <50 mg/dL (women) All patients 5-year total CVD event rate (%) Hazard ratio: (95%) Cl: P-value: 0.89 ( ) P=0.035 Low HDL-C ( ) P=0.02 TG >150mg/dL ( ) P=0.07 Low HDL-C + TG>200 mg/dL ( ) P=0.01 Highest therapeutical benefit of fenofibrate in patients with elevated TG and low HDL cholesterol (FIELD study)

Triglycerides and CVD Epidemiological studies Intervention studies Pathophysiology of atherogenic dyslipidemia Niacin Fibrates Genes and genome-wide association studies

Nature Genetics 2008;40,161 GWAS Identify Genes Involved in Triglyceride Metabolism Associated 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- Major LDL Type TG Zheng C, Sacks F. JLR 2007;48: Slow clearance CIII Zheng C. Am J Clin Nutr 2008;88:272

Caron S & Staels B, Circ Res 2008 ApoCIII : a link between hypertriglyceridemia and vascular dysfunction? Triglyceride-rich Lipoproteins (Lp) TG-rich Lipo- proteins apoCIII Triglyceride Metabolism VLDL production TG metabolism TG-rich Lp/VLDL clearance TG-rich Lp/VLDL uptake Blood Adhesion molecule expression (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 Q1Q2Q3Q4 Q5 Triglycerides p= Q1Q2Q3Q4 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 Triglycerides and Coronary Artery Calcification Pollin T. et al. Science 2008;322, Age (years) Coronary Artery Calcification RR RX

Triglycerides and CVD Epidemiological studies Intervention studies Pathophysiology of atherogenic dyslipidemia Niacin Fibrates Genes and genome-wide association studies

The Metabolic Syndrome: a Major Health Problem

Control of plasma triglyceride metabolism Plasma TG apo A-V/apo CIII production LPL production Lipolytic activity /TG clearance sdLDL hepatic lipogenesis mitochondrial FA  -oxidation TG secretion

Insulin Resistance and Dyslipidemia  TG  Apo B  VLDL (large) (large) IA Fat Cells Insulin IR XLiver  FFA Cytokines LDL (CETP) TGCE (  HL) (  HL)  Small Dense LDL LDL CETG (CETP)  HDL 2 (  HL) Kidney Apo A-1 HDL 3 FFA: Free fatty acids CETP: Cholesteryl ester transfer protein HL: Hepatic lipase

Liver Adipocytes NEFA TG HSL Lipolysis HYPERGLYCEMIA HYPERINSULINEMIA FA TG Lipogenesis Esterification TG CM Gut  -oxidation VLDL Hepatic lipid accumulation is related to insulin resistance and associated with increased VLDL1 production

Triglycerides and CVD Epidemiological studies Intervention studies Pathophysiology of atherogenic dyslipidemia Niacin Fibrates Genes and genome-wide association studies 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 HDL 2 cholesterol Increased remnant lipoproteins

Causal factor with variation Glucose  Longterm monitoring HbA1c  TG  Remnants  HDL  Nordestgaard et al. Current Drug Targets, 2009, 10,