ΜΕΤΑΒΟΛΙΣΜΟΣ ΤΩΝ ΛΙΠΟΠΡΩΤΕЇΝΩΝ

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1 ΜΕΤΑΒΟΛΙΣΜΟΣ ΤΩΝ ΛΙΠΟΠΡΩΤΕЇΝΩΝ FFA Εξωγενής οδός Χυλομικρά LPL Υπολλείματα Χυλομικρών LRP Ήπαρ Έντερο Οδός ανάστροφης μεταφοράς χοληστερόλης LCAT Free Cholesterol Περιφερικοί Ιστοί Ήπαρ Nascent HDL HDL3 HDL2 LDL LDL-R SR-B1 LRP VLDL LPL IDL HL FFA Ενδογενής οδός

2 HDL metabolism Bile FC A-1 A-1 CE SR-B1 CE Mature HDL LCAT Tg FC Nascent HDL from liver or intestine ABC1 FC CE Macrophage CETP CE B CE VLDL/LDL

3 Framingham Study: DM and CHD Mortality 20-Year Follow-up Annual CHD Deaths per 1000 Persons DM Non-DM Men Women Kannel WB, McGee DL. JAMA. 1979;241:

4 % of Deaths Mortality in People with Diabetes Causes of Death Ischemic heart disease Other heart disease Diabetes Cancer Stroke Infection Other Geiss LS, et al. In: Diabetes in America. 2nd ed

5 Survival (%) Survival (%) Survival Post-MI in Diabetic and Nondiabetic Men and Women: Minnesota Heart Survey 100 MEN 100 WOMEN 80 No diabetes n= No diabetes n= Diabetes n= Diabetes n= Months Post-MI Months Post-MI Adapted from Sprafka JM, et al. Diabetes Care. 1991;14:

6 Age-adjusted CVD death rate per 10,000 person-years Influence of Multiple Risk Factors* on CVD Death Rates in Diabetic and Nondiabetic Men: MRFIT Screenees No diabetes Diabetes None One only Two only All three *Serum cholesterol >200 mg/dl, smoking, SBP >120 mmhg Stamler J, et al. Diabetes Care. 1993;16:

7 Ticking Clock Hypothesis For The clock starts ticking Microvascular complications At onset of hyperglycemia Macrovascular complications Before the diagnosis of hyperglycemia WHO. Diabetologia. 1985;28: Haffner SM, et al. JAMA. 1990;263:

8 Relative Risk of Myocardial Infarction or Stroke* Ticking Clock Hypothesis: Glucose Abnormalities Increase CV Risk: Data from the Nurses Health Study *Adjusted n = 1,508 diabetes at baseline n = 5,894 new-onset diabetes No Diabetes Before Diabetes Diagnosis After Diabetes Diagnosis Diabetes at Baseline CV = cardiovascular Hu FB, et al. Diabetes Care. 2002;25:

9 Stepwise Selection of Risk Factors* in 2693 White Patients with Type 2 Diabetes with Dependent Variable as Time to First Event: UKPDS Coronary Artery Disease (n=280) Position in Model First Second Third Fourth Fifth Variable Low-Density Lipoprotein Cholesterol High-Density Lipoprotein Cholesterol Hemoglobin A 1c Systolic Blood Pressure Smoking P Value < *Adjusted for age and sex. Turner RC, et al. BMJ. 1998;316:

10 People suffering events (%) 30 SIMVASTATIN: MAJOR VASCULAR EVENTS by YEAR in DIABETIC PATIENTS Logrank p< PLACEBO SIMVASTATIN Years of follow-up Benefit/1000(SE) -1(6) 13(8) 34(9) 47(10) 51(15) 58(48)

11 SIMVASTATIN: REVASCULARISATIONS and MAJOR VASCULAR EVENTS by prior DIABETES Vascular event SIMVASTATIN PLACEBO Rate ratio & 95% CI & disease group (10269) (10267) STATIN better PLACEBO better Revascularisations Diabetes 260 (8.7%) 309 (10.4%) No diabetes 679 (9.3%) 896 (12.3%) All patients 939 (9.1%) 1205 (11.7%) Major vascular events Diabetes 601 (20.2%) 748 (25.1%) No diabetes 1432 (19.6%) 1837 (25.2%) ALL PATIENTS 2033 (19.8%) 2585 (25.2%) 24% SE 4 reduction (2P< ) 24% SE 3 reduction (2P< )

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13 PPAR-α agonists reduce CV events in T2DM patients with high TG and low HDL % patients developing events % patients developing events FIELD: Sub-analysis :Total CV events in patients with Metabolic Syndrome 20 Fenofibrate Placebo 20 Fenofibrate Placebo % % TG>204 mg/dl 0 TG>204 mg/dl + Low HDL P=0.01 N=2517 P=0.005 N=2014 R Scott et al, Diabetes Care 32: , 2009

14 Globally, dyslipidemia is a widespread condition in diabetics Conclusion : Every 3 out of 4 diabetic suffers from dyslipidemia Selby JV et al. Am J Manag Care. 2004;10(part 2):

15 Clinical Manifestations of Insulin Resistance Visceral Adiposity Insulin Resistance Glucotoxicity; Lipotoxicity; Adiponectin Type 2 Diabetes Glycemic Disorders Dyslipidemia -Low HDL -Small, dense LDL -Hypertriglyceridemia Hypertension -Endothelial dysfunction/ inflammation (hs-crp) -Impaired thrombolysis ( PAI-1) Atherosclerosis HDL = high-density lipoprotein; hs-crp = high-sensitivity C-reactive protein; LDL = low-density lipoprotein; PAI-1 = plasminogen activator inhibitor-1

16 Macrophages Invade Visceral Adipose Tissue When Adipocytes Die Dead Adipocyte Weight Gain Obesity Lean Adipose Tissue (5% to 10% of cells are macrophages) Obese Adipose Tissue (Up to 50% of cells are macrophages)

17 Invading Macrophages in Visceral Fat Cinti S, et al. J Lipid Res. 2005;46:

18 Adipose Tissue Is an Endocrine Organ: Its Function in Health and Disease Lipoprotein lipase Hypertension Inflammation TNF CRP IL-6 Angiotensinogen Insulin Free Fatty Acids Resistin Atherogenic Dyslipidemia Adipsin (Complement D) Atherosclerosis Adiponectin Leptin Lactate Plasminogen activator inhibitor-1 (PA-1) Thrombosis Type 2 Diabetes CRP = C-reactive protein; IL-6 = interleukin-6; TNFα = tumor necrosis factor-alpha Reprinted in adapted form from Trayhurn P, Wood IS. Br J Nutr. 2004;92: , with permission of Cambridge University Press. Eckel RH, et al. Lancet. 2005;365: Lyon CJ, et al. Endocrinology. 2003;144:

19 Dyslipidemia in DM and IRS Elevated total TG Reduced HDL Small, dense LDL HDL 3 and HDL 1 and HDL 2 LDL is not usually high Postprandial Hyperlipemia

20 Dyslipidemia in DM and IRS Increased Triglycerides VLDL HDL Apo A-I Decreased LDL, sldl Apo B

21 Dyslipidemia based on TG and LDL 13% 11% 35% 35% Normal Lipids 41% TG, N LDL 13% TG, LDL 41% 11% N TG, LDL

22 Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - UKPDS Type 2 MEN Control Type 2 WOMEN Control Number of Pts TC (mg/dl) LDL-C (mg/dl) * 135 HDL-C (mg/dl) 39** 43 43* 55 TG (mg/dl) 159* * 95 * P<0.001, ** P<0.02 comparing type 2 vs. controll UKPDS Group. Diabetes Care 1997;20:

23 Dyslipidemias in Adults with Diabetes Framingham Heart Study MEN WOMEN Normal DM Normal DM Increased cholesterol 14% 13% 21% 24% Increased LDL 11% 9% 16% 15% Decreased HDL 12% 21% 10% 25% Increased triglycerides 9% 19% 8% 17% Garg A et al. Diabetes Care 1990;13:

24 Mechanisms of DM Dyslipidemia Fat Cells FFA Liver IR X Insulin

25 Mechanisms of DM Dyslipidemia Fat Cells FFA Liver IR X TG Apo B VLDL VLDL Insulin

26 Insulin Resistance and Lipoprotein Lipase Decreased insulin action on lipoprotein lipase leads to decreased uptake of TG -rich lipoproteins TG-rich Lipoproteins Lipoprotein lipase Decreased insulin action on hormone sensitive lipase enhanced lipolysis leading to FFA. In the presence of hyperinsulinaemia, FFA is used for VLDL synthesis by liver FFAs, glycerol Overproduction of VLDL adapted from: Haffner S, et al. Diabetes Care 1999;22:

27 Mechanisms of DM Dyslipidemia Fat Cells Liver FFA CE IR X TG Apo B VLDL VLDL (CETP) TG HDL (hepatic lipase) Apo A-1 Insulin Kidney

28 Mechanisms of DM Dyslipidemia Fat Cells Liver FFA CE IR X Insulin TG Apo B VLDL CE VLDL (CETP) LDL (CETP) TG TG HDL SD LDL (hepatic lipase) Apo A-1 Kidney (lipoprotein or hepatic lipase)

29 LDL Subclass Phenotypes in Diabetes Mellitus LDL Subclass n A Int B Men* Diabetic Nondiabetic Percent Women** Diabetic Nondiabetic * Feingold KR et al. Arterioscler Thromb 1992; 12: ** Selby JV et al. Circulation 1993; 88:

30 Atherogenicity of small dense LDL

31 Structure of HDL Apo A-I Surface Monolayer of Phospholipids and Free Cholesterol Apo A-II Hydrophobic Core of Triglyceride and Cholesteryl Esters Rye KA, et al. Atherosclerosis. 1999;145:

32 Heterogeneity of HDL Particle Shape Apolipoprotein Composition Discoidal Spherical A-I HDL A-I/A-II HDL A-II HDL Particle Size Lipid Composition TG, CE, and PL HDL 2b HDL 2a HDL 3a HDL 3b HDL 3c Rye KA, et al. Atherosclerosis. 1999;145:

33 HDL Prevents Formation of Foam Cells Monocyte Vessel Lumen LDL Adhesion Molecules MCP-1 LDL Endothelium Cytokines Modified LDL Macrophage Foam Cell HDL Promote Cholesterol Efflux Intima Miyazaki A, et al. Biochim Biophys Acta. 1992;1126:73-80.

34 HDL Inhibits the Oxidative Modification of LDL Monocyte LDL Vessel Lumen Adhesion Molecules Cytokines MCP-1 LDL Modified LDL Endothelium HDL Inhibits Oxidation of LDL Macrophage Foam Cell HDL Promotes Cholesterol Efflux Intima Mackness MI, et al. Biochem J. 1993;294:

35 Inhibition of Adhesion Molecules Monocyte HDL Inhibits Adhesion Molecule Expression LDL Vessel Lumen Adhesion Molecules Cytokines MCP-1 LDL Modified LDL Endothelium HDL Inhibit Oxidation of LDL Macrophage Foam Cell HDL Promotes Cholesterol Efflux Intima Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15:

36 Recruitment of Blood Monocytes by Endothelial Cell Adhesion Molecules Monocyte Rolling Sticking Vessel Lumen Transmigration E-Selectin VCAM-1 ICAM-1 MCP-1 Endothelium Intima Charo IF. Curr Opin Lipidol. 1992;3:

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38 CARDS: Primary End Point Major CV Events* Acute Coronary Heart Disease Events, Coronary Revascularization, or Stroke Cumulative Hazard (%) 15 n # of Events End of Treatment Median LDL Placebo Atorvastatin 10 mg 10 5 Atorva 10 mg 1, mg/dl Placebo 1, mg/dl 37% Relative Risk Reduction (P=0.001) (95% CI: 17 52) 0 47% Non-fatal MI Risk Reduction 2 (P=0.0178) % Years 3.9 Trial Stopped Early 4.75 The study was stopped 2 years earlier than anticipated after a median follow up of 3.9 years, due to beneficial effect of atorvastatin The results were similar in patients with LDL-C <120 mg/dl (3.1 mmol/l) and 120 mg/dl (3.1 mmol/l) 1. Adapted from Colhoun HM, et al. Lancet. 2004;364: Data on File, Pfizer Inc.

39 Cumulative Hazard (%) CARDS: Cumulative Hazard for Stroke 4 3 Placebo Atorvastatin10 mg Placebo n=39 [31% of all first CVD events] 48% Relative Risk Reduction Cumulative Hazard for Stroke 2 (P=0.016) Years from Randomization Atorvastatin n=21 [25% of all first CVD events] Adapted from Newman C, et al. Presented at: American Heart Association 2005 Scientific Sessions; November 13-16, 2005; Dallas, TX.

40 Major Vascular Event Rate, % Acute CVD Event Rate, % Residual CVD Risk in Patients With Diabetes Treated With Statins HPS: Patients With Diabetes N = 5963 CARDS N = % Risk 20.2 Reduction 12 32% Risk Reduction Residual CVD Risk 6 4 Residual CVD Risk Placebo Simvastatin Collins R et al. Lancet. 2003;361: Placebo Atorvastatin CARDS, Collaborative Atorvastatin Diabetes Study. Colhoun HM et al. Lancet. 2004;364:

41 Suboptimal HDL-C Levels Substantially Increase CHD Risk at all LDL-C Levels CHD relative risk Framingham Heart Study ,9 1,2 0,6 0,9 0,3 0,4 0,7 0,1 0,2 0,3 2.6 mmol/l 4.1 mmol/l 5.7 mmol/l 1,5 2,9 0.6 mmol/l 1.2 mmol/l 1.7 mmol/l 2.2 mmol/l HDL-C LDL-C The independent effect of raising HDL-C and lowering triglycerides on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Systolic blood pressure=135 mmhg Adapted from Kannel WB. Am J Cardiol. 1987;59:80A 90A.

42 Triglycerides and CVD Factor Recent Meta- Analysis of 29 Studies Groups CHD Cases Duration of follow-up 10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 CHD Risk Ratio* (95% CI) N = Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 Overall CHD Risk Ratio* TRG κατά 100mg/dl 70% Decreased Risk κινδύνου κατά 1 Increased Risk 1.72 ( ) Sarwar N, et al. Circulation. 2007;115:

43 Primary Outcome Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event Fenofibrate Placebo (N=2765) (N=2753) N of Rate N of Rate Events (%/yr) Events (%/yr) HR (95% CI) P Value ( ) 0.32

44 Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Primary Endpoint: Subgroup HHS (Gemfibrozil) -34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > % BIP (Bezafibrate) -7.3% (0.24) TG > 200 mg/dl -39.5% FIELD (Fenofibrate) -11% (0.16) TG > 204 mg/dl HDL-C < 42 mg/dl -27% ACCORD (Fenofibrate) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31%

45 ΜΕΤΑΒΟΛΙΚΕΣ ΔΙΑΤΑΡΑΧΕΣ ΣΤΗΝ ΟΥΡΑΙΜΙΑ Αναιμία Υπερουριχαιμία Νεφρική οστεοδυστροφία Οξέωση Υπερκαλιαιμία Δυσλιπιδαιμία Καχεξία

46 mg/dl EΠΙΠΕΔΑ ΛΙΠΙΔΙΩΝ ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΧΝΑ Total Cholesterol Triglycerides Control < > 3.0 Serum Creatinine (mg/dl) Fliser D, et al. Kidney Int 1998

47 Down-regulation of tissue lipoprotein lipase expression in experimental chronic renal failure Vaziri ND, et al. Kidney Int 1996

48 Secondary hyperparathyroidism downregulates lipoprotein lipase expression in chronic renal failure Vaziri ND, et al. Am J Physiol Renal Physiol 1997

49 Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure Kim C, et al. Kidney Int 2005

50 ΜΕΤΑΒΟΛΙΣΜΟΣ ΤΩΝ ΛΙΠΟΠΡΩΤΕЇΝΩΝ FFA Εξωγενής οδός Χυλομικρά LPL Υπολλείματα Χυλομικρών LRP Ήπαρ Έντερο Οδός ανάστροφης μεταφοράς χοληστερόλης Free Cholesterol Περιφερικοί Ιστοί Ήπαρ Nascent HDL LCAT HDL3 HDL2 LDL LDL-R SR-B1 LRP VLDL LPL IDL HL FFA Ενδογενής οδός

51 HDL metabolism Bile FC A-1 A-1 CE SR-B1 CE Mature HDL LCAT Tg FC Nascent HDL from liver or intestine ABC1 FC CE Macrophage CETP CE B CE VLDL/LDL

52 Plasma phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase in end-stage renal disease (ESRD) Pahl MV, et al. Nephrol Dial Transplant 2009

53 Lipoprotein (a) or [Lp(a)]

54 Lipoprotein(a) Serum Concentrations and Apolipoprotein(a) Phenotypes in Mild and Moderate Renal Failure Kronenberg F, et al. J Am Soc Nephrol 2000

55 ΔΥΣΛΙΠΙΔΑΙΜΙΑ ΤΗΣ ΧΡΟΝΙΑΣ ΝΕΦΡΙΚΗΣ ΝΟΣΟΥ Χυλομικρά Τριγλυκερίδια HDL-χοληστερόλη VLDL Remnants-IDL Lp(a) [ανάλογα με το φαινότυπο] LDL-χοληστερόλη [ small, dense LDL]

56 ΔΥΣΛΙΠΙΔΑΙΜΙΑ ΤΗΣ ΧΡΟΝΙΑΣ ΝΕΦΡΙΚΗΣ ΝΟΣΟΥ Παράγοντες που τροποποιούν τα φαινοτυπικά χαρακτηριστικά Αιτιολογία της ΧΝΑ Βαρύτητα της λευκωματουρίας Μέθοδος υποκατάστασης νεφρικής λειτουργίας Φαρμακευτική αγωγή

57 ΔΥΣΛΙΠΙΔΑΙΜΙΑ TOY ΝΕΦΡΩΣΙΚΟΥ ΣΥΝΔΡΟΜΟΥ μικτή δυσλιπιδαιμία VLDL LDL 2 φαινότυποι αμιγής υπερχοληστερολαιμία LDL Παράγοντες που ενδέχεται να καθορίζουν το φαινότυπο: Βαρύτητα λευκωματουρίας Βαρύτητα έκπτωσης νεφρικής λειτουργίας

58 ΑΡΧΙΚΗ ΥΠΟΘΕΣΗ Λευκωματουρία Υπολευκωματιναιμία Μείωση ογκωτικής πίεσης Αύξηση παραγωγής αλβουμίνης και λιποπρωτεϊνών από το ήπαρ

59 Down-regulation of hepatic LDL receptor expression in experimental nephrosis Vaziri N, et al. Kidney Int 1996

60 Gene expression of lipoprotein lipase in experimental nephrosis Liang K, et al. J Lab Clin Med 1997

61 mg/dl Elevated Plasma Lipoprotein (a) in Patients with the Nephrotic Syndrome Patients Control S1 S2 S3 S4 S5 apo (a) isoform Wanner C, et al. Ann Intern Med 1993

62 Estimated 3-Year All-Cause and Cardiovascular Disease (CVD) Mortality by Cholesterol Level Liu, Y. et al. JAMA 2004;291:

63 ΕΠΙΔΡΑΣΗ ΤΩΝ ΣΤΑΤΙΝΩΝ ΣΤΟΝ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΚΙΝΔΥΝΟ ΑΤΟΜΩΝ ΜΕ ΗΠΙΑ ΚΑΙ ΜΕΤΡΙΑ ΕΚΠΤΩΣΗ ΝΕΦΡΙΚΗΣ ΛΕΙΤΟΥΡΓΙΑΣ STUDY DRUG Number of patients with CKD RR reduction LIPS fluvastatin % Pooled analysis of 30 trials fluvastatin % CARE pravastatin % PPP pravastatin % TNT atorvastatin % ALLIANCE atorvastatin %

64 Proportion suffering event (%) SHARP: Major Atherosclerotic Events Risk ratio 0.83 ( ) Logrank 2P= Placebo Eze/simv Years of follow-up

65 4D study in diabetic hemodialysis patients: no benefit of statin therapy 60 Placebo Cumulative incidence of primary endpoint (%) Atorvastatin p= No. at risk: Time (years) Placebo Atorvastatin D=Die Deutsche Diabetes Dialyse Studie Wanner C et al. N Engl J Med 2005; 353:

66 AURORA: primary endpoint Kaplan-Meier estimate of time to first major CV event Placebo Cumulative incidence of primary endpoint (%) Rosuvastatin HR=0.96 (95% CI ) P= No. at risk: Years from randomization Rosuvastatin Placebo

67 ΑΙΤΙΑ ΔΕΥΤΕΡΟΠΑΘΟΥΣ ΔΥΣΛΙΠΙΔΑΙΜΙΑΣ Σακχαρώδης διαβήτης: TRG, HDL-C Χρόνια νεφρική ανεπάρκεια: TRG, HDL-C Νεφρωσικό σύνδρομο: Υποθυρεοειδισμός: TCHOL, LDL-C, TRG TCHOL, LDL-C, TRG Πρωτοπαθής χολική κίρρωση: TCHOL Φάρμακα

68 ΦΑΡΜΑΚΑ ΠΟΥ ΑΥΞΑΝΟΥΝ ΤΑ ΕΠΙΠΕΔΑ ΤΗΣ LDL-CHOL Διουρητικά Κυκλοσπορίνη Αμιοδαρόνη ω-3 λιπαρά οξέα Αντιρετροϊκά φάρμακα Γλιταζόνες

69 ΦΑΡΜΑΚΑ ΠΟΥ ΑΥΞΑΝΟΥΝ ΤΑ TRG Β-αποκλειστές Διουρητικά Ιντερφερόνη Ρετινοειδή Οιστρογόνα-Ταμοξιφαίνη Άτυπα αντιψυχωσικά

70 ΑΙΤΙΑ ΔΕΥΤΕΡΟΠΑΘΟΥΣ ΔΥΣΛΙΠΙΔΑΙΜΙΑΣ Σακχαρώδης διαβήτης: Υποθυρεοειδισμός: Νεφρωσικό σύνδρομο: Χρόνια νεφρική ανεπάρκεια: Πρωτοπαθής χολική κίρρωση: γλυκόζη νηστείας TSH γενική ούρων κρεατινίνη ορού, egfr αλκαλική φωσφατάση