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Pr. SELIM JAMBART Chef du service d’endocrinologie et des maladies métaboliques

Stratégies pour atteindre les objectifs de contrôle lipidique. Stratégies pour atteindre les objectifs de contrôle lipidique. Pr. SELIM JAMBART Chef du service d’endocrinologie et des maladies métaboliques Hôtel-Dieu de France. The past two decades were dominated by LDL and statin therapy.

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Pr. SELIM JAMBART Chef du service d’endocrinologie et des maladies métaboliques

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  1. Stratégies pour atteindre les objectifs de contrôle lipidique Stratégies pour atteindre les objectifs de contrôle lipidique Pr. SELIM JAMBART Chef du service d’endocrinologie et des maladies métaboliques Hôtel-Dieu de France

  2. The past two decades were dominated by LDL and statin therapy.

  3. Substantial residual cardiovascular risk in statin-treated patients The MRC/BHF Heart Protection Study 30 Placebo Statin 20 Risk reduction=24% (p<0.0001) 19.8% of statin-treatedpatients had a majorcardiovascular event by 5 years % patients 10 0 0 1 2 3 4 5 6 Year of follow-up Heart Protection Study Collaborative Group, 2002

  4. Residual risk after statin treatment in major intervention trials Risk of primary event (%)

  5. room for improvement

  6. room for improvement • Furthereventsreductionthrough: • More aggressive LDL-C lowering

  7. Is Lower Better? 4S-P Secondary prevention Primary prevention 25 20 15 10 5 0 Simvastatin Pravastatin Lovastatin LIPID-P 4S-S % with CHD event CARE-P CARE-S LIPID-S WOSCOPS-P ? WOSCOPS-S AFCAPS-S AFCAPS-P 50 70 90 110 130 150 170 190 210 LDL-C (mg/dL) S = statin treated; P = placebo treated.

  8. 0 30 3 6 9 12 15 18 21 24 27 Prove It: All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 16% RR (P = 0.005) 10 5 0 Months of Follow-up

  9. room for improvement • Furthereventsreductionthrough: • More aggressive LDL-C lowering • Targetingotherlipoproteins

  10. 60 50 40 30 Frequency (%) 20 10 0 ALP Frequency of different forms of dyslipidemiain men with coronary artery disease FH Low HDL FCHL Hyper CT polygenic Homocys Lp(a) ALP:  TG,  HDL-c + small, dense LDL Superko HR. Circulation 1996;94:2351-4

  11. Classification desdyslipidémies • Une dyslipidémie ne représente pas une seule maladie, mais comprend des situations pathologiques différentes par leur pathogénie et donc par leur traitement

  12. Classification desdyslipidémies • 1/ Dysfonction du récepteur des LDL LDL-C élevé; CT élevé; TG et HDL-C normaux

  13. CELLS LPL Lipoprotein lipase LPL Lipoprotein lipase LDL HL Hepatic lipase HL Hepatic lipase receptor LPL LDL IDL IDL IDL LPL HL LDL receptor Small Small HL LPL VLDL VLDL Liver Large Large VLDL VLDL

  14. THE LDL RECEPTOR

  15. LDL:anatherogenic lipoprotein

  16. The Framingham Study: Relationship Between Cholesterol and CHD Risk 150 125 100 CHD incidence per 1000 75 50 25 0 <204 (<5.3) 205-234 (5.3–6.1) 235-264 (6.1–6.8) 265-294 (6.8–7.6) >295 (>7.6) Serum total cholesterol, mg/dL (mmol/L) Adapted from Castelli WP. Am J Med 1984;76:4–12

  17. StatinsMolecular mechanisms of actionSREBP feedback control

  18. 4S-P Secondary prevention Primary prevention 25 20 15 10 5 0 Simvastatin Pravastatin Lovastatin LIPID-P 4S-S % with CHD event CARE-P CARE-S LIPID-S WOSCOPS-P WOSCOPS-S AFCAPS-S AFCAPS-P 50 70 90 110 130 150 170 190 210 LDL-C (mg/dL) S = statin treated; P = placebo treated.

  19. LDL-C Targets for Therapy LDL-C target(mg/dL) Patient category No CHD, < 2 other risk factors No CHD, > 2 other risk factors < 20% 10 year risk CHD and CHD risk equivalents < 160 mg/dL < 130 mg/dL < 100 mg/dL ? 70 mg/dl Noncoronary atherosclerosis Diabetes > 20% 10 year CHD risk JAMA 2001;285:2486-2497.

  20. Cholesterol Absorptiongood absorbers and bad absorbers ABCA1 ABCA1=adenosine triphosphate–binding cassette protein; ACAT=acyl-coenzyme A:cholesterol acyltransferase; CM=chylomicron Adapted fromChampe PC, Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.

  21. Ezetimibe Blocks Cholesterol Metabolism at a New Site Plaque formation Bile acids CE Synthesis Free cholesterol Remnants DIET Unstirred water layer BLOOD Cholesterol Brush Border ENTEROCYTE X X FC biosynthesis Cholesteryl Ester (CE) Sterols/ stanols FC CE ACAT Micelles X Chylomicrons Cholesterol Absorption Inhibitors (ezetimibe)

  22. Pleiotropic parietal vascular effects of statins

  23. Ezetimibe potentializes statins effecton cholesterol Plaque formation Bile acids CE X Synthesis Free cholesterol Remnants Statins DIET Unstirred water layer BLOOD Cholesterol Brush Border ENTEROCYTE FC biosynthesis Cholesteryl Ester (CE) FC CE ACAT Micelles X Chylomicrons Cholesterol Absorption Inhibitors (ezetimibe)

  24. Classification desdyslipidémies • 1/ Dysfonction du récepteur des LDL • LDL-C élevé; CT élevé; TG et HDL-C normaux • 2/ Dysfonction de la LPL • Triade • Triade

  25. CELLS LPL Lipoprotein lipase LPL Lipoprotein lipase LDL HL Hepatic lipase HL Hepatic lipase receptor LPL LDL IDL IDL IDL LPL HL LDL receptor Small Small HL LPL VLDL VLDL Liver Large Large VLDL VLDL

  26. Diabetes and the metabolic syndrome: a typical atherogenic lipoprotein profile Small, denseLDL  TG HDL-c Prandial lipemia

  27. TG-rich lipoproteins C-rich lipoproteins Atherogenicapo B-rich particles In people with the triade profile we should consider the quality of lipoproteins rather than the quantity of blood lipids (the busses rather than the passengers) CHYLO VLDL β VLDL IDL LDL Small dense LDL

  28. Hyper TG, Low HDL-C Small dense LDL

  29. CORONARY HEART DISEASE Visceral Obesity Elevated fibrinogen,tissue factor & PAI 1 Non alcoholic fatty liver Polycistic ovaries Impaired glucosetolerance; type 2 DM Hyperuricemia High blood pressure Microalbuminuria Hyper TG, Low HDL-C Small dense LDL HYPERINSULINISM INSULIN RESISTANCE GENES ENVIRONMENT Syndrome X=Polymetabolic syndrome=Deadly quartet=Dyslipidemic hypertension

  30. Classical risk factors  GLU  BP  LDL-C SMOKING AGE MALE SEX GLOBAL CARDIOMETABOLIC RISK

  31. HDL-C TNF IL-6 AbdominalObesity Glu TG PAI-1 Emerging risk factors Classical risk factors  GLU  BP BP  LDL-C SMOKING AGE MALE SEX Insulin T2DM Metabolic syndrome GLOBAL CARDIOMETABOLIC RISK

  32. 36% 8.1% Total Diabetes High-Risk WaistCircumference in Men (>40 in) (Diagnosed/ Undiagnosed) Despite Therapeutic Advances, Prevalence of Risk Factors Remains NHES/NHANES data 40 1960-1962 1971-1975 26.4% 1976-1980 30 1988-1994 1999-2000 17% 14.9% 20 Prevalence (%) 10 0 High Total High Blood Pressure Smoking Cholesterol (Systolic >140 mm Hg (240 mg/dL) or Diastolic >90 mm Hg) Gregg EW, et al. JAMA. 2005;293:1868-1874. Ford ES, et al. Obes Res. 2003;11:1223-1231.

  33. Metabolic Syndrome Associated With Increased CV Morbidity and Mortality No metabolic syndrome 25 25 Metabolic syndrome * * P <0.001 20 20 * * P <0.001 15 15 * Prevalence (%) Mortality Rate (%) 10 10 * * 5 5 0 0 CHD MI Stroke All-Cause Cardiovascular * Mortality Mortality *Cardiovascular mortality was defined using ICD-9 (codes 390-459) before 1997 and ICD-10 (codes 100-199) thereafter. Isomaa B, et al. Diabetes Care. 2001;24:683-689.

  34. PPARa discovery elucidatesthe mechanism of action of fibrates

  35. Regulation of lipoprotein metabolism by PPARa Fibrates PPAR PPAR PPARa RXR RXR A-I PPRE PPRE LPL PPAR PPAR RXR RXR C-III A-II PPRE PPRE TG rich particles HDL particles • Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC, Circulation, 1998, 98, 2088-2093

  36. PPARa activators lower small dense LDL PPARa activator VLDL rich in apo C-III VLDL poor in apo C-III Cholesteryl ester TG CETP Cholesteryl ester CETP LDL Large buoyant LDL TG Small dense LDL LDL receptor Macrophage

  37. PPARa activators act on the main factorsinvolved in the onset of atherosclerosis

  38. HHS: CHD events reduced in patients with high TG levels and LDL/HDL ratio 71% reduction p < 0.005 LDL/HDL ≤5 LDL/HDL >5

  39. Placebo Placebo 20 20 Bezafibrate Bezafibrate 16 16 12 12 8 8 4 4 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 BIP: event rate reduction in patients with baseline triglycerides < or >200 mg/dl (2.3 mmol/L) Triglycerides < 200 mg/dl Triglycerides  200 mg/dl p = 0.86 p = 0.02 39.5% reduction Rate (%) Rate (%) Time (years) Time (years)

  40. 0 10 20 Cumulative event rate change (%) 30 40 VA-HIT: CVD risk reduction in diabetics compared with nondiabetics Combined endpoint CHD death Stroke Nonfatal MI 3 p = 0.88 10 p = 0.67 18 p = 0.07 21 22 p = 0.09 p = 0.17 32 Diabetes p = 0.004 No diabetes p = 0.26 40 41 p = 0.046 p = 0.02

  41. FIELD: Effects on CHD Events* and Total CVD Risk in Patients With No Prior CVD (n=7664) CHD Events* Total CVD 0 -5 -10 Risk reduction (%) -20 -19% -25% p=0.004 p=0.014 -30 (n = 7664) (n = 7664) * Post-hoc analysis

  42. Visceral obesity • Insulin resistance, prediabetes or diabetes • Primary prevention • Lipids goal (NECP ATP III) • LDL cholesterol <100 mg/dl • HDL cholesterol > 40 mg/dl • Triglycerides <150 mg/dl The fibrates patients in association withstatins if necessary

  43. VLDL TG + Alcohol; fructose Beta blockers; furosemide Oral synthetic estrogens

  44. Total cholesterol 200 200 • HDL cholesterol 50 30 • Triglycerides 100 350 • LDL cholesterol 130 100 • Total cholesterol 200 200 • HDL cholesterol 50 30 • Triglycerides 100 350 • LDL cholesterol 130 100 • Non HDL cholesterol150 170

  45. Classification desdyslipidémies • 1/ Dysfonction du récepteur des LDL • LDL-C élevé; CT élevé; TG et HDL-C normaux • 2/ Dysfonction de la LPL • Triade • 3/ Hypo HDLémies isolées

  46. Apo A1 ABCA1 The reverse cholesterol transport Cell SRB1 Liver membrane LDL receptor FC CE CE VLDL, IDL, LDL LPL LCAT CETP HDL3 HDL2 TG Peripheral tissues Free cholesterol FC TG Triglycerides CE Cholesteryl esters LCAT Lecithin cholesterol acyltransferase CETP Cholesteryl ester transfer protein

  47. Therapy of low HDL-C levels • Lifestyle changes • PPAR αagonists: fibrates • PPAR γ agonists: glitazones • Statins • Nicotinicacid • CETP inhibitors • ? Sibutramine • ? Rimonabant • Apo A 1 Milano

  48. Apo A1 ABCA1 Reverse cholesterol transportis a three steps process Cell SRB1 Liver membrane LDL receptor FC CE CE VLDL, IDL, LDL LPL LCAT CETP HDL3 HDL2 TG Peripheral tissues Free cholesterol FC TG Triglycerides CE Cholesteryl esters LCAT Lecithin cholesterol acyltransferase CETP Cholesteryl ester transfer protein

  49. Relationship betweencholesteryl ester transferprotein (CETP) and atherosclerosis • CONFUSING AND CONFLICTING REPORTS

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