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Bart Staels

Triglycerides as a Risk Factor for Cardiovascular Disease. Bart Staels. INSERM UR545; Institut Pasteur de Lille; Université Lille Nord de France Lille, France. Triglycerides and CVD. • Epidemiological studies. • Intervention studies. • Niacin. • Fibrates.

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Bart Staels

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  1. Triglycerides as a Risk Factor for Cardiovascular Disease Bart Staels INSERM UR545; Institut Pasteur de Lille; Université Lille Nord de France Lille, France

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

  3. Are triglycerides an independent risk factor? PROCAM Study 200 150 Mls/ 1000/ 10 years 100 >165 Triglycerides Tertiles (mg/dL) 50 < 104-165 < 104 0 <132 132-162 >162 LDL-Cholesterol tertiles (mg/dL)

  4. Triglyceride Level Is An Independent CVD Risk Factor Recent Meta-analysis of 29 Studies Groups CHD Cases CHD Risk Ratio* (95% CI) N=262 525 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 1.72 (1.56-1.90) Overall CHD Risk Ratio* Decreased Risk Increased Risk 1 2 *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) Sarwar N, et al. Circulation. 2007;115:450–458

  5. Myocardial infarction in CCHS 100 Women 80 N=7600 Triglycerides Follow-up: 28 years (mmol/L) (440 mg/dL) ³ 5 60 Cumulative incidence (%) 2 - 3 < (<90) 1 40 20 0 0 50 60 70 80 90 100 Age (yr) Nordestgaard et al. JAMA 2007

  6. High triglycerides contribute to the residual risk after statin treatment 25 20.3 20 RR0.64 (0.53-0.78) P=0.001 13.5 15 30-day risk of death, MI Or recurrent ACS (%) 10 5 0 >200 (n=603) <200 (n=2,796) on-treatment TG (mg/dL) 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;51:724

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

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

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

  10. Statin+niacin vs statin+ezetimibe on lipids – ARBITER 6 Taylor et al, NEJM, 361:2113-2122, 2009

  11. 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) Taylor et al, NEJM, 361:2113-2122, 2009

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

  13. apo C-III production apo A-V production TG clearance sdLDL Fibrates control triglyceride and remnant-lipoprotein metabolism Fibrates Liver PPARa m i t o c h o n d r i a l F A b - o x i d a t i o n T G s e c r e t i o n Plasma TG

  14. 292 13.0% 3.9% 71% <.005 MS dyslipidemia 1470 18.4% 14.1% 25% .03 MS 769 24.5% 32% 36.5% .004 Diabetics 13.5% 26% MS Dyslipidemia 2014 17.8% 0.007 Fibrates decrease CV risk in patients with metabolic syndrome and diabetic dyslipidemia Diabetic dyslipidemia or Metabolic Syndrome subgroups vs overall population Major CVD Event Rate Trial N Control Drug Rel. RR P Primary Prevention HHS 4081 4.1% 2.7% 34% <.02 Secondary Prevention BIP 3090 15.0% 13.6% 9.4% .26 VA-HIT 2531 21.7% 17.3% 22% .006 Mixed (Primary+Secondary) FIELD 9795 10.4% 11% 11.7% .16

  15. 0.85 (0.74-0.97) P=0.02 0.88 (0.75-1.01) P=0.07 0.74 (0.59-0.92) P=0.01 17.8 15.4 15.1 13.6 13.5 13.0 TG >150mg/dL Low HDL-C + TG>200 mg/dL Low HDL-C Highest therapeutical benefit of fenofibrate in patients with elevated TG and low HDL cholesterol (FIELD study) Hazard ratio: (95%) Cl: P-value: 0.89 (0.80-0.99) P=0.035 20 15 13.9 12.5 5-year total CVD event rate (%) 10 5 0 All patients *HDL-c: <40 mg/dL(men) and <50 mg/dL (women) Scott R et al Diabetes Care 2009; 32:493-498

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

  17. 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 Nature Genetics 2008;40,161

  18. 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 ++ TG ++ - ++ TG Slow clearance - -CIII Dense LDL CIII- Major LDL Type Zheng C, Sacks F. JLR 2007;48:1190 Zheng C. Am J Clin Nutr 2008;88:272

  19. Endothelial cells Monocytes Adhesion molecule expression (VCAM-1,ICAM-1) 1-integrin expression NO production TLR2 activation Monocyte adhesion on ECs vasoconstriction Endothelial dysfunction – Inflammation Micro- & Macrovascular diseases (CVD) ApoCIII : a link between hypertriglyceridemiaand vascular dysfunction? Triglyceride-rich Lipoproteins (Lp) TG-rich Lipo- proteins Blood apoCIII TG metabolism TG-rich Lp/VLDL clearance TG-rich Lp/VLDL uptake VLDL production Triglyceride Metabolism Caron S & Staels B, Circ Res 2008

  20. Multivariate 3.5 Apo CIII in VLDL+ LDL 3.0 2.5 p=0.04 RR 2.0 1.5 1.0 0.5 Triglycerides (NS) 0.0 Q5 Q1 Q2 Q3 Q4 Triglycerides and Apo CIII in VLDL and LDL to Predict CHD CARE Univariate 3.5 3.0 2.5 Triglycerides RR 2.0 1.5 p=0.03 1.0 0.5 0.0 Q5 Q1 Q2 Q3 Q4 Sacks, Alaupovic, et al. Circulation 2000;102:1886

  21. ApoCIII Genetic Variant Correlates with Triglycerides and Coronary Artery Calcification 8000 RR 7000 RX 6000 5000 Coronary Artery Calcification 4000 3000 2000 1000 0 29 39 49 59 69 79 89 99 Pollin T. et al. Science 2008;322,1702 Age (years)

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

  23. The Metabolic Syndrome:a Major Health Problem

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

  25. IA Fat Cells Liver FFA Cytokines CE ( HL)  TG Apo B (CETP) HDL2 VLDL (large) HDL3 X IR TG Apo A-1 (CETP) CE TG Kidney Insulin LDL  Small DenseLDL LDL ( HL) Insulin Resistance and Dyslipidemia FFA: Free fatty acids CETP: Cholesteryl ester transfer protein HL: Hepatic lipase

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

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

  28. 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

  29. TG Remnants HDL Causal factor with variation Longterm monitoring HbA1c Glucose Nordestgaard et al. Current Drug Targets, 2009, 10, 328-335

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