Ipercolesterolemia familiare: come riconoscerla, come trattarla?

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1 Ipercolesterolemia familiare: come riconoscerla, come trattarla? Claudio Bilato UOC di Cardiologia, ULSS 5 Ovest Vicentino

2 Il caso: Paola, 54 anni, non precedenti di rilievo; Giunge in PS per comparsa di dolore toracico oppressivo, intensità 7/10, retrosternale, irradiato alla base del collo, associato a sudorazione ed astenia, no cardiopalmo, no dispnea, insorto nel pomeriggio verso le rincasando in bicicletta dal lavoro, temporaneamente regredito con il riposo per ripresentarsi acuto alle 21 circa dopo cena, per cui allertava il 118; la sintomatologia migliorava in ambulanza dopo nitrati s.l. obiettività cardiovascolare, polmonare e neurologica negative Esami urgenti: emocromo, PT, INR, ionemia, funzionalità renale, D-dimero nella norma, hs-pcr 2,8 mg/l, Troponina I: 4,3 ng/ml (v.n. <0.015)

3 ECG

4 Coro/PCI primaria Prima Dopo

5 Decorso e dimissione Picco troponina alla 12 ora dall ingresso pari a 10,3 ng/ml, Emocromo, formula leucocitaria, VES, PT, INR, ionemia, funzionalità renale ed epatica, glicemia, profilo proteico plasmatico, esame urine nella norma. TSH nella norma, CT 348 mg/dl, LDL-C 290 mg/dl, HDL-C=45 mg/dl, TG 64 mg/dl. Ecocardio Va post PCI: tutto Ventricolo Sn di forma, bene? volume e spessori parietali nella norma, lieve ipocinesia segmenti infero-posteriore, FE 61%, sezioni destre nella norma. Aorta bulbo ed ascendente nella norma, noduli calcifici su cuspidi aortiche. Esame Doppler nella norma EcoDoppler TSA: lesione in parte calcifica a margini regolari, al bulboorigine della carotide sinistra con stenosi del 55%. IMT max 1,8 mm a Dx Dimessa in V giornata con diagnosi di: STEMI inferiore in paziente dislipidemica e con terapia con: ASA 100 mg/die, clopidogrel 75 mg/die, atorvastatina 80 mg/die, metoprololo 50 mg due volte al dì, ramipril 2,5 mg due volte al dì.

6 Anamnesi e obiettività clinica Padre deceduto per IMA a 61 anni, PTCA a 54 anni, iperteso, ipercolesterolemico; zio paterno by-pass AC a 58 anni, IMA a 64, fumatore; un fratello di 51 sottoposto a TEA carotide dx a 50 anni, ipercolesterolemico in terapia, un secondaria? fratello di 47 anni riferito sano; classica paziente in prevenzione In menopausa da due anni, no HRT il colesterolo è solo fattore di rischio Nessuna patologia di rilievo da segnalare, talora fastidio tipo o «tendinite» è «la all'achilleo malattia» sn dopo che tennis; ha riferisce portato riscontro alla di ipercolesterolemia ( 360 mg/dl) dall età di circa 30 anni trattata con dieta (mai data eccessiva importanza) coronaropatia precoce? xantoma al tendine d Achille sinistro, ed ispessimento dell achilleo destro

7 Se la paziente fosse affetta da ipercolesterolemia familare? Consensus Statement of the EAS, European Heart Journal, 2013

8 Se la paziente fosse affetta da ipercolesterolemia familare? Consensus Statement of the EAS, European Heart Journal, 2013

9 Se la paziente fosse affetta da ipercolesterolemia familare? Consensus Statement of the EAS, European Heart Journal, 2013

10 Ipercolesterolemia familare (FH): patologia genetica clinicamente riconoscibile Patologia genetica, autosomica dominante 1 Comunemente dovuta a mutazioni del gene per il recettore delle LDL 2,3 che conduce a ridotta clearance delle LDL nel plasma 1 Altre mutazioni note includono il gene per Apo B e PCSK9 Manifestazioni cliniche 1,2 Grave ipercolesterolemia da accumulo di LDL Accumulo di colesterolo nei tendini (xantomi), pelle ed occhi (xantelasmi, gerontoxon) Evidenza di patologia cardiovascolare precoce 1. Marais AD. Clin Biochem Rev. 2004; 2. Mahley RW, Williams Textbook of Endocrinology. 2008; 3. Rader DJ, J Clin Invest. 2003

11 Nel ns. caso vi sono elementi di sospetto? Familiarità per CHD prematura (padre, zio) Padre e fratello ipercolesterolemici (quali valori?) La nostra paziente con CHD prematura (54 anni) Presenza di xantomi tendinei nella paziente Valori elevati di LDL-C (290 mg/dl), senza statina

12 Ipercolesterolemia Familiare Eterozigote Criteri per la Diagnosi del Dutch Lipid Clinic Network (DLCN) Consensus Statement of the EAS, European Heart Journal, 2013

13 Nella nostra paziente Score DLCN= 14 Diagnosi CERTA di Ipercolesterolemia Familiare! Consensus Statement of the EAS, European Heart Journal, 2013

14 The most cost-effective approach for identification of new FH subjects is cascade screening of family members of known index cases

15 Ipercolesterolemia Familiare: le dimensioni del problema patologia sotto-diagnosticata e sotto-trattata Numero di pazienti FH (basato su prevalenza 1/500) 33,300 Netherlands 9,900 Norway 600 Iceland 15,600 Switzerland 123,000 United Kingdom 92,200 Spain 22,200 Belgium 10,900 Slovakia 11,100 Denmark 100,000 South Africa Australia 14,100 Hong Kong 130,900 France 46,300 Taiwan 121,000 Italy 5,700 Oman 621,200 USA 68,600 Canada 254,800 Japan 34,300 Chile 381,500 Brazil 214,900 Mexico FH diagnosticati (stima) 71% 43% 19% 13% 12% 6% 4% 4% 4% 3% 1% 1% 1% 1% <1% <1% <1% <1% <1% <1% <1% <1% FH diagnosticati, % basata sulla prevalenza nazionale stimata Consensus Statement of the EAS, Eur Heart J, 2013

16 Prevalence of Definite or Probable FH According to the DLCN * Criteria Prevalence (%) Copenhagen General Population Study by 20-year age class and gender based on individuals PREVALENZA REALE (1/200- RISPETTO 1.0 WomenA QUELLA STIMATA 1/100 Men /133 (1/500)! 0.5 1/ ): SUPERIORE 1/400 In Italia 0 circa pazienti con FH all Age (years) Prevalence (ratio) Benn et al. JCEM 2012;97:

17 CHD risk as function of the DLCN Criteria for a Diagnosis of FH in Individuals Off Lipid-lowering Medication from the General Population No. di partecipanti No. di CHD Odds ratio (95% CI) FH improbabile 58,158 2,592 1 (reference) FH possibile 3, ( ) FH certa o probabile ( ) X Se non trattati, gli uomini e le donne con Ipercolesterolemia Familiare eterozigote vanno incontro a eventi cardiovascolari prima di 50 e 55 anni rispettivamente Benn, J Clin Endocrinol Metab 2012

18 Cumulative Burden of LDL-C in Individuals With and Without FH as Function of Age Homozygous FH Heterozygous FH Accumulation of LDL-C mmol/l/years yrs 35 yrs Age (Years) No FH 55 yrs Women Threshold for CHD Smoking Hypertension Diabetes Triglycerides HDL-C Lp(a) Starr, Clin Chem Lab Med 2008 Huijgen, Circ Cardiovasc Genet 2012

19 1334 patients with premature (<55 year in men, <60 year in women) CAD admitted to a Department of Cardiology Definite or probable FH 54% Possible or unlikely FH 46% On statin therapy 38% Not on statin therapy 62% Watts, Heart, Lung and Circulation 2012

20 Cumulative Burden of LDL-C in Individuals With and Without FH as Function of Age Homozygous FH Heterozygous FH Accumulation of LDL-C mmol/l/years yrs 35 yrs Age (Years) No FH 55 yrs Women Threshold for CHD Smoking Hypertension Diabetes Triglycerides HDL-C Lp(a) Starr, Clin Chem Lab Med 2008 Huijgen, Circ Cardiovasc Genet 2012

21 Ipercolesterolemia familiare: come trattarla statine + ezetimibe inibitori della PCSK9 lopitamide aferesi delle LDL

22 Ipercolesterolemia familiare: goal di trattamento LDL-C FH senza CVD (rischio CV elevato) LDL-C < 100 mg/dl FH Target #1 in tutte le Linee Guida FH con CVD (rischio CV molto elevato) LDL-C < 70 mg/dl Pazienti FH: NON vanno utilizzate le carte del rischio (es. SCORE) ESC/EAS Guidelines - Eur Heart J 2011

23 Cumulative coronary heart disease-free survival among patients with FH according to statin treatment P<0.001 absolute risk of first onset of coronary heart disease was 11/1000 person year in statin treated patients compared with 119/1000 person year in untreated patients. after adjustment for year of birth and sex, statin treated patients had a 76% reduction in risk of coronary heart disease compared with untreated patients BMJ 2008;337:a2423

24 Riduzione del colesterolo LDL con le statine disponibili a vari dosaggi Reduction to reach an Reduction to reach an Solo Baseline LDL-C 1 LDL-C su Target 5 <100 mg/dl pazienti LDL-C Target <70 mg/dl HeFH >200 >50% >50% % >50% FH raggiunge % >50% i target LDL-C>50% di LDL-C raccomandati! LDL-C<50% Medium High Statin dose* Statins Ezetimibe

25 LDL-C Reduction with Statin Monotherapy and Statin Plus Ezetimibe: GRAVITY Ballantyne CM et al. Presented at EAS, 2013

26 Primary Endpoint ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke HR CI (0.887, 0.988) p=0.016 Simva 34.7% 2742 events NNT= 50 EZ/Simva 32.7% 2572 events 7-year event rates

27 Gli inibitori della PCSK9 (Proprotein Convertase Subtilisin-like Kexin type 9) Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels PCSK9 Gain of Function = Less LDLRs PCSK9 Loss of Function = More LDLRs

28 Hepatic LDLRs Play a Central Role in Cholesterol Homeostasis Elaborated from 1. Brown MS, et al. Proc Natl Acad Sci 1979;76: Elaborated from 2. Qian YW, et al. J Lipid Res. 2007;48: Elaborated from 3. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:

29 Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles Elaborated from 1. Brown MS, et al. Proc Natl Acad Sci 1979;76: Elaborated from 2. Qian YW, et al. J Lipid Res. 2007;48: Elaborated from 3. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:

30 PCSK9 Regulates the LDLRs Surface Expression by Targeting for Lysosomal Degradation Elaborated from 1. Brown MS, et al. Proc Natl Acad Sci 1979;76: Elaborated from 2. Qian YW, et al. J Lipid Res. 2007;48: Elaborated from 3. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:

31 LDLR and PCSK9 Expression Are Both Upregulated When Intracellular Cholesterol Levels Are Low *[SREBP] = sterol regulatory element-binding protein. Elaborated from 1. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29: Elaborated from 2. Dubuc G, et al. Arterioscler Thromb Vasc Biol. 2004;24:

32 Blockade of PCSK9/LDLR Interaction May Lower LDL Levels Elaborated from Chan JC, et al. Proc Natl Acad Sci U S A. 2009;106:

33 Inibitori della PCSK9 nome azienda tipo Evolocumab Alirocumab Bococizumab Amgen Sanofi/Regeron Pfizer Anticorpo umano Anticorpo umano Anticorpo umanizzato

34 Evolocumab: studi di fase II trials pazienti posologia LAPLACE- TIMI 57 MENDEL RUTHER- FORD GAUSS Iper CT (LDL > 85 mg/dl) on top di statine + ezetimibe Iper CT (LDL mg/dl) no terapia o ezetmibe FH eterezigoti (LDL > 100 mg/dl) in statine + ezetimibe Alto rischio CVS intolleranti alle statine; + ezetimibe mg s.c. ogni 2-4 wks per 12 wks mg s.c. ogni 2-4 wks per 12 wks mg s.c. ogni 4 wks per 12 wks mg s.c. ogni 4 wks per 12 wks % calo LDL ref Lancet 2012 Lancet 2012 Circul 2012 JAMA 2012

35 Studi di fase III trials farmaco pazienti % LDL reduction DESCARTES LAPLACE-2 evolocumab evolocumab Iper CT + on statine + ezetimibe Iper CT on top di statine vs ezetimibe o placebo MENDEL-2 evolocumab Iper CT no statine vs ezetmibe RUTHER- FORD-2 GAUSS-2 TESLA B ODYSSEY mono evolocumab evolocumab evolocumab alirocumab FH eterezigoti in statine + ezetimibe intolleranti alle statine vs ezetimibe FH omozigoti in statine + ezetimibe Iper CT no statine vs ezetmibe -57% in 52 weeks % in 12 weeks % in 12 weeks % in 12 weeks -70% in 12 weeks -31% in 12 weeks -32% in 24 weeks

36 Long Term Odyssey trial (a post-hoc analysis) CHD death, non-fatal MI, ischaemic stroke, unstable angina LDL-C -61% +0.8% placebo n=788 p<0.01 HR =.46 (95% CI 0.26 to 0.82) alirocumab (150 mg every 2 wks) n= weeks 2,341 patients with hypercholesterolaemia at very high risk, including patients with heterozygous FH (18%), who were on maximally tolerated statin therapy (44% on high-dose intensive statin therapy) with or without other lipid lowering treatment. Baseline LDL cholesterol was 3.2 mmol/l (122 mg/dl). ESC meeting 2014

37 DESCARTES: Treatment Emergent Adverse Events n (%) Placebo N = 302 Evolocumab N = 599 Any Treatment Emergent Adverse Event 224 (74.2) 448 (74.8) Serious 13 (4.3) 33 (5.5) Adjudicated atherosclerotic CV events 2 (0.7) 6 (1.0) Death 0 (0.0) 2 (0.3) Leading to discontinuation of study drug 3 (1.0) 13 (2.2) Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study New Engl J Med 2014

38 n (%) DESCARTES: Treatment Emergent Adverse Events II Most Common Treatment Emergent AEs Placebo N = 302 Evolocumab N = 599 Nasopharyngitis 29 (9.6) 63 (10.5) Upper respiratory tract infection 19 (6.3) 56 (9.3) Influenza 19 (6.3) 45 (7.5) Back pain 17 (5.6) 37 (6.2) Neurocognitive AEs* 2 (0.7) 1 (0.2) Amnesia - Short-term memory loss 0 (0.0) 1 (0.2) Dementia With Lewy Bodies 1 (0.3) 0 (0.0) Encephalopathy 1 (0.3) 0 (0.0) Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study * Searched HLGT terms: Deliria (incl confusion); cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and perception; mental impairment disorders New Engl J Med 2014

39 DESCARTES: Hepatic and Muscle Safety n (%) Liver function tests Placebo N = 302 Evolocumab N = 599 ALT or AST > 3 ULN* 3 (1.0) 5 (0.8) ALT or AST > 5 ULN* 1 (0.3) 3 (0.5) Muscle TEAEs and Laboratory Results Myalgia 9 (3.0) 24 (4.0) CK > 5 ULN* 1 (0.3) 7 (1.2) CK > 10 ULN* 1 (0.3) 3 (0.5) * At any visit post baseline, TEAE = Treatment emergent adverse event New Engl J Med 2014

40 DESCARTES: Glycemic Parameters Change from baseline at week 52 Placeb o Evolocumab Diet alone A 10 mg/d A 80 mg/d A 80 mg/d + E10 mg/d n Glucose, (mg/dl); mean (SE) 0.4 (0.9) -0.5 (1.5) 1.7 (1.2) 0.3 (1.0) 2.6 (1.9) n HbA1C, (%); mean (SE) A = Atorvastatin E = Ezetimibe 0.00 (0.03) 0.09 (0.04) 0.04 (0.02) 0.02 (0.03) 0.09 (0.04) New Engl J Med 2014

41 Riduzione di C-LDL -50% Dopo 24 settimane on the top of statin Iniezione sottocute ogni 15 gg Morte coronarica, IMA non fatale, stroke, angina instabile -50% Eventi avversi non differenti tra trattamento e placebo 84 weeks

42 Lopitamide: inibisce la Microsomal Triglyceride Transfer Protein (MTP) e quindi la sintesi di VLDL e chilomicroni Liver Cell Apo B100 MTP Nascent VLDL TG Cytoplasm ER Lumen VLDL Blood Vessel LDL Intestinal Epithelial Cell Apo B48 MTP Nascent Chylomicron TG Cytoplasm ER Lumen Chylomicron Chylomicron Remnant Hussain, J Lipid Res 2003

43 Riduzione del LDL-C dopo 26 settimane in 29 pazienti FH con Lopitamide Percent Change from Baseline # 27/29 patients had a history of CVD at baseline 10 (35%) of 29 patients had undergone CABG surgery 5 of these patients were 21 years of age 3 patients under the age of 8 at the time of open-heart surgery 3 patients had undergone multiple CABG procedures Coronary angioplasty was performed in 3 patients (10%) Aortic valve replacement in 3 patients (10%) Mitral valve replacement or repair in 3 patients (10%) Patient ID Lomitapide Dose (mg) Mean Median 5 (n=3) 10 (n=2) 20 (n=6) 40 (n=7) 60 (n=11) Received apheresis # Patient was a responder at later time points during the study. Patients discontinued from the study. Numbers over the bars are baseline LDL-C in mg/dl Data on File, Aegerion Pharmaceuticals

44 Efficacy Phase Safety Phase Mean % Change from Baseline (95%CI) Study Week % of patients with Gastrointestinal events Study Week Cuchel, Lancet 2013

45 Aferesi delle LDL

46 Effetti della rimozione extracorporea delle LDL Schuff-Werner, Clin Res Cardiol 2012

47 L aferesi delle LDL riduce gli eventi coronarici nei pazienti con ipercolesterolemia familiare Lui, J Lipids 2014

48 *p< Leebmann, Circulation 2013

49 Ipercolesterolemia Familiare: sottodiagnosticata e sottotrattata E possibile fare diagnosi clinica!! Solo 1 su 5 FH a target per LDL-C La maggior parte dei pazienti FH necessita di ridurre il LDL-C di >60% Molti FH in statina + ezetimibe a dosi insufficienti per raggiungere i target di LDL-C Nuovi farmaci molto promettenti

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