Μια πρόσφατη επίσκεψη στις κατευθυντήριες

Transcription

1 Μια πρόσφατη επίσκεψη στις κατευθυντήριες οδηγίες για τις νέες τοποθετήσεις ως προς τους παράγοντες κινδύνου για τη στεφανιαία νόσο. HDL-C και Lp(a) Γεώργιος Γκουμάς MD, PhD, FESC Αν. Διευθυντής Β Καρδιολογικής Κλινικής, Ευρωκλινική Αθηνών Αντιπρόεδρος Ομάδας Εργασίας Επιδημιολογίας, Πρόληψης και Μεταβολικού Συνδρόμου Ελληνικής Καρδιολογικής Εταιρείας

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4 Residual risk after statin treatment in major intervention trials Risk reduction (%) Residual risk ASCOT-LLA PROSPER HPS WOSCOPS LIPID CARE AFCAPS/TexCAPS 4S CARDS Risk of primary event (%) Kastelein JJP, 2005 December 2005

5 Lp(a) consists of a cholesterol-rich rich LDL particle with one molecule of apo B-100 B and a molecule of apo a Nordestgaard B G et al. Eur Heart J 2010;eurheartj.ehq386

6 Typical distributions of lipoprotein(a) levels in the general population (CGPS) N~3000 N~3000 About 20% of people are thought to have plasma Lp(a) levels over 50 mg/dl Nordestgaard B G et al. Eur Heart J 2010

7 Determinants of Lp (a) levels wide variability between individuals but stable within individuals No difference between women and men Physical exercise and diet do not have any impact Alcohol consumption might lower Lp (a) Mainly determined genetically depending on Apo (a) genotype Apo (a) genotype distributions vary widely between populations Caucasians, Chinese, Japanese predominantly low levels Hispanics intermediate levels Africans higher levels

8 Elevated Lp(a) Levels In Patients with Hypothyroidism Lipoprotein(a) Levels, U/L P<.005 Elevated lipoprotein(a) levels are associated with an increased risk of CAD development and MI occurrence Patients with mild thyroid failure have higher lipoprotein(a) levels, which increases their risk of CAD 0 Patients With Mild Thyroid Failure Control Group* PROCAM. Lipoprotein(a) and cardiovascular risk. Kung AW, et al. Clin Endocrinol. 1995;43:

9 Lipoprotein(a) Levels, mg/dl Lp(a) Concentrations in Patients With Renal Failure *p<0.005 *p<0.01 *p<0.01 Hemodialysis CAPD Chronic RF Controls CAPD, continuous ambulatory peritoneal dialysis; RF, renal failure * vs. controls Milionis H et al. Am J Kidney Dis 1999;33:1100-6

10 Risk ratios of coronary heart disease by quantiles of usual lipoprotein(a) levels. Risk ratio and 95% CI (log scale) Usual Lp(a) (mg/dl) Geometric mean (log scale) Nordestgaard B G et al. Eur Heart J 2010

11 Serum Lp(a) and Risk for Ischemic Stroke 3,5 3 2,88 3,2 2,5 Odds ratio 2 1, ,83 1,5 0, Lp(a) quintile Milionis H et al. Atherosclerosis 2006;187:

12 Lp(a) and pathogenesis of vascular disease via prothrombotic/anti-fibrinolytic effects as apolipoprotein(a) possesses structural homology with plasminogen and plasmin but has no fibrinolytic activity and via accelerated atherogenesis as a result of intimal deposition of Lp(a) cholesterol

13 Lp (a): Consensus Paper by the European Atherosclerosis Society

14 Recommendations: Lp(a) measurement Lp(a) should be measured once in all subjects at intermediate or high risk of CVD/CHD who present with premature CVD familial hypercholesterolemia a family history of premature CVD and/or elevated Lp(a) recurrent CVD despite statin treatment 3% 10-year risk of fatal CVD according to the European guidelines 10% 10-year risk of fatal and/or non-fatal CHD according to the US guidelines Nordestgaard B G et al. Eur Heart J 2010

15 Effect of Niacin on Lp(a) levels Niacin reduces Lp(a) levels by up to 30 40% in a dose- dependent manner [1-3g/d] In n addition, exerts other potential beneficial effects by - LDL cholesterol - Total cholesterol - Triglycerides - Remnant cholesterol - HDL cholesterol Chapman MJ et al. Pharmacol Ther 2010;126:314-45

16 Other potent therapies for lowering Lp(a) Inhibitors of CETP (anacetrapib) Antisense oligonucleotides (mipomersen) Thyroid hormone analogue therapies LDL-apheresis

17 Structure of HDL apoa-i Surface Monolayer of Phospholipids and Free Cholesterol apoa-ii Hydrophobic Core of Triglyceride and Cholesteryl Esters Rye KA et al. Atherosclerosis 1999;145:

18 Framingham Heart Study CAD Risk as a Function of LDL and HDL in Men Coronary Artery Disease (CAD) Relative Risk mg/dl mmol/l mg/dl mmol/l HDL Cholesterol (HDL-C) LDL Cholesterol (LDL-C) Modified from Castelli WP. Can J Cardiol 1988;4:5A 10A.

19 Impact of Increases in HDL-C on CAD Risk Reduction

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21 METANALYSIS OF STATIN TRIALS Statins do not eliminate risk of low HDL in statin-treated treated patients after adjustment for LDL a 10-mg/dL increase in HDL prevented 7.6 MIs and 9.7 cardiovascular-disease disease events per 1000 patient-years this benefit was nearly identical in healthy controls R Karas et al AHA 2009 Scientific Sessions; November 18, 2009; Orlando, FL.

22 METANALYSIS OF RANDOMIZED TRIALS Should we treat low HDL? Meta-regression analysis including 108 randomised trials (half of them were statin trials) involving participants at risk of cardiovascular events With all trials included, change in HDL explained almost no variability (<1%) in any of the outcomes (CHD events, CHD deaths, or total deaths) Briel M et al. BMJ 2009; 338: b92

23 In this post hoc analysis, HDL cholesterol levels were predictive of major cardiovascular events in patients treated with statins This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter

24 The Lancet July 2010 HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial PM Ridker et al HDL concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL

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26 It is not the increase or decrease in plasma HDL-C concentration per se that critically determines the atherosclerotic risk Its functional (proinflammatory and antiinflammatory) properties are more important

27 HDL and atherosclerosis Risk of coronary events Change in quantity Change in quality HDL-cholesterol (mmol/l)

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29 Odds Ratios for Coronary Artery Disease According to Efflux Capacity and Selected Risk Factors Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima ima media thickness and the likelihood of angiographic coronary artery ry disease, independently of the HDL cholesterol level. Khera AV et al. N Engl J Med 2011;364:

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31 Raising HDL-C: Statins (Cont d)

32 Fibrates: Mechanism of action Activation of PPARα modulates the expression of target genes Increase ApoA and HDL activates ABCA1 Reduction of FFA and TG Modestly decrease LDL if TG not high Shift away from the small dense LDL phenotype

33 Consistent Benefit of Fibrate Treatment across all 5 randomized trials in the subgroups with high triglycerides and low HDL!

34 PROactive subgroup analysis: Outcomes in patients with type 2 diabetes and previous MI End point Pioglitazone (n=1230), n Placebo (n=1215), n Hazard ratio (95% CI) p Time to fatal/ nonfatal MI ( ) 0.99) Time to ACS ( ) 0.97) TG 11% HDL 18% Erdmann E. American Heart Association Scientific Sessions 2005; Nov 13-16, 2005; Dallas, TX.

35 Drugs acting as PPAR agonists in development as treatments for atherosclerosis Name/Number Company Tesaglitazar (Galida) Stage of development Type of PPAR AstraZeneca Phase 3 Alpha/ gamma GW GlaxoSmithKline Phase 2 Alpha GW GlaxoSmithKline Phase 2 Delta K-111 Roche Phase 1 Alpha GW GlaxoSmithKline Phase 1 Alpha LY-674 Ligand Phase 1 Mixed LY-929 Ligand Phase 1 Mixed GW Ligand Phase 1 Alpha/ gamma LY Lilly Preclinical Alpha DRF-4832 Dr Reddy's Preclinical Alpha/ gamma Source: Pharmaprojects

36 Niacin: Mechanism of action Inhibits lipolysis in adipocytes and thereby reduces serum non-esterified fatty acid levels all atherogenic lipoproteins LDL (-8%)( Favorable effects on LDL-particle density VLDL and chylomicrons (-25%)( Lp(a)(-20%) HDL (+29%)

37 The Coronary Drug Project (CDP): Fifteen Year Follow-up

38 Most patients on Niacin ER do not reach therapeutic doses of 2g 100 Ασθενείς υπό θεραπεία, % > 1500 mg mg mg mg 500 mg 0 Ν= 4 εβδομ εβδομ εβδομ εβδομ Έτος Kamal-Bahl S, Burke T, Watson D et al. Dosage and titration patterns of extended release niacin in clinical practice. Abstract presented at the 7th American Heart Association Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke; May 2006; Washington, DC, USA.

39 Effectiveness of niacin ER 2g g versus 1g Dose Mean % change from baseline LDL-C HDL-C TG 1g / day g g / day

40 Laropiprant reduces moderate to extreme ERN- induced flushing to placebo levels by week GFSS 4 (mean % days) Study week ERN 1 g ERN 2 g ERN LRPT (pooled) + ERN Placebo ERN = extended-release niacin; GFSS = Global Flushing Severity Score; LRPT = laropiprant. Paolini JF et al. Am J Cardiol. 2008;101:

41 ARBITER 6-HALTS LDL<100 mg/dl (84 mg/dl and 81 mg/dl in the niacin- and ezetimibe-treatment treatment arms, respectively) moderately low HDL (<50 men,<55 women, average 42 mg/dl)

42 Niacin MRI study 71 patients with low HDL (<40 mg/dl), carotid atherosclerosis, peripheral arterial disease, or type 2 DM and CAD 2 g daily nicotinic acid or placebo, on top of statin therapy Lee JMS et al. J Am Coll Cardiol 2009; 54:

43 AIM-HIGH study (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes) a five-year trial with 3300 patients with atherogenic dyslipidemia treated with simvastatin alone or simvastatin with extended- release niacin

44 HPS2 THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) Whether ER niacin/laropiprant reduces CVD events vs placebo in high risk CVD patients already on treatment (simvastatin 40mg or ezetimibe/simvastatin 10/40mg)

45 CETP-inhibitors

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48 DEFINE Study Anacetrapib (100 mg) or placebo in 1623 participants who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines LDL HDL Lp(a) By 76 weeks By 24 weeks 81 mg 45 mg (39.8% reduction) 41 mg 101 mg (138.1% increase) 36.4% reduction no changes in BP,electrolyte or aldosterone levels Cardiovascular events in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P=0.40)

49 The million dollar question: Will a 130% increase of HDL plus LDL- reduction of 40 % lead to less CAD events?

50 REVEAL HPS-3 3 TIMI-55 trial will include coronary heart disease patients treated with statin therapy and anacetrapib or placebo will take at least four years to complete ( ) 2016)

51 The ASSERT Trial

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53 ERASE Trial

54 A First-in in-man, Randomized, Placebo-Controlled Study to Evaluate the Safety and Feasibility of Autologous Delipidated HDL Plasma Infusions in Patients With ACS serial autologous infusions of selective HDL delipidated plasma are clinically feasible and well tolerated The IVUS data demonstrated a numeric trend toward regression in the total atheroma volume of ± mm3 in the delipidated group versus an increase of total atheroma volume of 2.80 ± mm3 in the control group (p = 0.268) R Waksman et al JACC 2010 Jun 15;55(24):

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56 HDL and exercise 7 P=0.015 HDL mainly when TG high HDL only with intense, frequent exercise HDL more in women than men Changes in HDL-C Concentration (mg/dl) Control Frequent, intense exercise Infrequent exercise Moderate Intense -2 Couillard C et al. Arterioscler Thromb Vasc Biol 2001;21: Kraus WE et al. N Engl J Med 2002;347: Copyright 2002 Massachusetts Medical Society. All rights reserved.

57 Weight and HDL-C Inverse correlation between body weight and HDL-C C is consistently observed in both men and women For every 3 kg of weight loss, HDL-C C levels increase 1 mg/dl Low-fat diet may decrease HDL Dattilo AM, Kris-Etherton PM. Am J Clin Nutr 1992;56:

58 Mediterranean Diet increases HDL

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60 Smokers have HDL-C C levels 7 20% 7 lower than nonsmokers. HDL-C C levels return to normal within days after smoking cessation

61 Thank you for your attention!