Hypolipidaenic treatment: From the past to the future

Transcript

1 University of Athens Medical School, Department of Cardiology, Hippokration General Hospital, Athens, Greece Hypolipidaenic treatment: From the past to the future Dimitris Tousoulis Professor of Cardiology

2 Conflict of interest Honorarium for invited presentations from BAYER-ELPEN PHIZER GALENIKA AMGEN NOVARTIS

3 Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal. Michael Brown and Joseph Goldstein Nobel Lectures (1985)

4 Cholesterol and Atherosclerosis Virchow ( ), observed that the artery walls of patients dying of occlusive vascular disease, such as myocardial infarction, were often thickened and irregular, and contained a yellowish fatty substance. This pathological condition was termed atheroma The Framingham study, established an increasingly strong correlation between high plasma cholesterol and CHD mortality Kannel WB. 1995;92: The Seven Countries Study showed that northern European countries and the United States had both high plasma cholesterol and high CHD mortality rates Keys A, et al. Prev Med. 1984;13:141 54

5 Lipid Hypothesis Elevated total, or more accurately LDL, cholesterol was causally related to coronary disease Whether reducing cholesterol would reduce the risk of myocardial infarction and other coronary events remain controversial until Statins introduction

6

7 Recommendations for treatment targets of LDL-C Main objective: LDL. Very high-risk patients: < 70 mg/dl ( level of evidence in I A ) High-risk patients: < 100 mg/d ( IIa A ). Moderate-risk patients: < 115 mg/dl ( IIa C ). Reduction of at least 50% of basal levels European Heart Journal 2011;32(14): Atherosclerosis 2011 Jul; 217(1): 3-46

8

9

10 STATINS

11 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

12 First statins Dr Akira Endo & Dr Masao Kuroda Inhibition of HMG-COA reductase the rate-limiting enzyme in the cholesterol biosynthetic pathway Yamamoto, A., H. Sudo, and A. Endo Atherosclerosis 35:

13 Mechanisms of Statins Action Inhibition of the Mevalonate Pathway Inhibition of Cholesterol Synthesis Inhibition of Isoprene synthesis

14 Lipid-Lowering Actions Lipid-lowering actions of Statins was first confirmed in patients with familial hypercholesterolemia and CAD Havel RJ et al. Ann Intern Med Nov;107(5):

15

16 Secondary prevention Trial Study design Treatment dose Key eligibility criteria 4S Secondary prevention Simvastatin mg yrs, prior angina or AMI, fasting total chol mmol/l CARE Secondary prevention, multicenter Pravastatin 40 mg yrs, prior AMI, fasting LDL chol mmol/l LIPID Secondary prevention, multicenter, mean f/u 6.1 years Pravastatin 40 mg yrs, prior AMI or unstable angina, fasting total chol 4 7 mmol/l GISSI prevention MIRACL Secondary prevention multicenter, mean f/u 23 months Secondary prevention, multicenter, 16 weeks f/u Pravastatin 20 mg Recent MI (<6 months), total cholestrol > 5.18 mmol/l Atorvastatin 80 mg >18 yrs, unstable angina or non-q-wave AMI Serruys study (LIPS) Secondary prevention, multicenter, median f/u 3.9 years Fluvastatin 80 mg yrs, pts with stable or unstable angina or silent ischemia who underwent PCI, tot chol mmol/l SPARCL Secondary prevention, multicenter, median f/u 4.9 years Atorvastatin 80 mg >18 yrs, prior ischemic or hemorrhagic stroke or TIA, LDL chol mmol/l FLORIDA Secondary prevention, multicenter, median f/u 1 year Fluvastatin 80 mg >18 yrs, AMI, total chol 6.5 mmol/l AVERT Secondary prevention, multicenter, f/u 18 months Atorvastatin 80 mg vs. PCI Stable CAD, stenosis of 50% in at least one coronary artery, LDL 3.0 mmol/l, triglycerides 5.6 mmol/l

17 Primary prevention Trial Study design Treatment dose Key eligibility criteria WOSCOPS AFCAPS/ TexCAPS HPS Primary prevention, one center, mean f/u 4.9 years Primary prevention, multicenter, mean f/u 5.2 years Primary and secondary prevention, multicenter, mean f/u 5 years Pravastatin 40 mg Lovastatin mg Simvastatin 40 mg yrs, no prior AMI, fasting LDL chol mmol/l yrs (males) or (females), no prior AMI, fasting LDL chol mmol/l yrs, with coronary disease, other occlusive arterial disease, or diabetes, with non-fasting tot chol of 3.5 PROSPER Primary and secondary prevention, multicenter, mean f/u 3.2 years Pravastatin 40 mg yrs, with history of or risk factors for vascular disease ASCOTTLLA Primary prevention, multicenter, median f/u 3.3 years Atorvastatin 10 mg yrs, hypertensive pts with at least 3 additional CHD risk factors, non-fasting total chol <6.5 mmol/l ALLHATLLT Primary and secondary prevention, multicenter, mean f/u 4.8 years Pravastatin 40 mg >55yrs with stage 1 or 2 hypertension & one additional CHD risk, fasting LDL mmol/l for no known CHD vs mmol/l for known CHD ALERT Primary and secondary prevention, multicenter, mean f/u 5.1 years Fluvastatin 40 mg yrs, prev renal or combined renal and pancreas transplants, tot chol mmol/l in pts with no CHD vs mmol/l for known CHD CARDS Primary prevention, multicenter, median f/u 3.9 years Atorvastatin 10 mg yrs, with type 2 diabetes and at least one of: retinopathy, albuminuria, current smoking, or hypertension; LDL 4.14 mmol/l

18 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

19 The Genesis of Pleiotropic Hypothesis PROVE IT TIMI 22 study, suggested dual mechanisms of benefit of statin therapy, LDL-c lowering and a direct antiinflammatory effect independent of LDL-c lowering, reflected by reduction of hscrp. N Engl J Med Jan 6;352(1):20-8 JUBITER study concluded that patients without cardiovascular risk factors and low LDL-c levels can benefit from statins treatment if they have increased levels of hscrp N Engl J Med Nov 20;359(21):

20 Tousoulis D... et al JACC 2014

21 Pleiotropic effects Reactive hyperemia-thrombosis-fibrinolysis

22 Pleiotropic effects Low-dose atorvastatin treatment modifies inflammatory process in patients with unstable angina and low cholesterol level, an effect seen at 6 weeks but not 1 week after admission Tousoulis et al. Int J Cardiol Apr 28;109(1):48-52.

23 Pleiotropic effects Circulation. 2011;124:

24

25 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

26 Statins and DM

27 Statins and DM

28 Statins and DM Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials 13 Trials/ pts One incident of DM every 225 pts treated for 4 years with statins Lancet Feb 27;375(9716):735-42

29 Statins and DM Favorable effects on glucose-loading induced elevation of glucose levels

30 Statins and DM

31 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

32 Statins and Cancer Risk Controversial results

33 Statins and Cancer Risk Beneficial effects after heart transplantation

34 Statins and Chemotherapy Related Complications

35 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

36 Statins and Dementia The Heart Protection Study, investigated the effect of simvastatin (40 mg daily) on cognitive function in 20,536 participants. After a mean follow-up period of 5.3 years, no significant change in cognitive function was shown between simvastatin- and placebo treated patients (43) Shepherd J et al. Lancet 2002;360: The JUPITER study reported no difference in cognitive function between rosuvastatin and placebo users at the end of the trial N Engl J Med Nov 20;359(21): The PROSPER investigated, in 5,804 participants, the effect of pravastatin (40 mg daily) on cognitive function the decrease in cognitive function over time was no different between pravastatin treatment versus placebo Collins R, et al. Lancet 2004;363:

37 Statins and Dementia

38 Statins and Dementia

39 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

40 Statins and HF

41 Statins and HF CORONA trial

42 Statins and HF

43 Statins and HF

44 Statins and HF

45 Statins and HF

46 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

47 Statins and CIN

48 Statins and CIN Statin Therapy Prevents the Development of Contrast-induced Nephropathy in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes Tousoulis D, Lazaros G et al. unpublished data

49 Statins and CKD

50 STATINS Cholesterol and atherosclerosis Statins in CVD prevention Beyond lipids effects Statins and Diabetes Statins and Cancer Statins and Dementia Statins and Heart failure Statins and CKD Statins in CAD and PAD

51

52 Statins STEMI

53 STATIN + EZETIMIBE

54 Η εζετιμίμπη και οι στατίνες έχουν συμπληρωματικό μηχανισμό δράσης 1 Together, ezetimibe in combination with a statin provides: Δεξαμένή χοληστερόλης (μυκήλια) NPC1L1 X Εζετιμίμπη Σταίνες Remnant Receptors HMG-CoA X Cholesterol 1 Cholesterol Pool CMR 1 Ελάττωση ηπατικής χοληστερόλης 2 Αυξημένη έκφραση υποδοχέων LDL 3 Αυξημένη κάθαρση της LDL-C από το πλάσμα Ήπαρ 2 Έκφραση LDL υποδοχέων 3 CM Αίμα LDL- C Atheroma NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnant. 1. Grigore L et al. Vas Health Risk Manag. 2008;4:

55 Διπλή Αναστολή για την αντιμετώπιση της χοληστερόλης Αναστολή της απορρόφησης της χοληστερόλης σύνθεση Αναστολή της σύνθεσης της χοληστερόλης απορρόφηση Διπλή Αναστολή 80% 21% -50% -38% -22% -25% απορρόφηση σύνθεση σύνθεση LDLc 15-20% 25-45% 45-65% απορρόφηση

56

57 Η έντονη ελάττωση της LDL-c μειώνει σημαντικά τα μείζονα καρδιαγγειακά συμβάντα (PROVE IT-TIMI 22) Wiviott S.D et al J Am Col Cardiol 2005;46:

58 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 6,4 % RRR EZ/Simva 32.7% 2572 events 7-year event rates N Engl J Med 2015

59 THE FUTURE

60 LDL - C Control in High-Risk Patients Americans who are high-risk (NCEP) and on lipid-modifying therapy ~½ have diabetes only ~½ have overt vascular disease Achieved LDL-C % % <70 28% Circulation. 2016;133:e38-e360

61 Τι είναι η PCSK9? Η Proprotein convertase subtilisin/kexin type 9 ή PCSK9 είναι μία φυσικά παραγόμενη πρωτείνη που συντίθεται στο ηπατοκύτταρο 1,2 Επίσης βρίσκεται και σε άλλα όργανα όπως έντερο, ΚΝΣ και νεφρός 1,2 Σύντομη παραμονή στο πλάσμα(<10 min); Αφαίρεση από το πλάσμα βασικά μέσω του LDLR 1,2 Η PCSK9 έχει ρόλο κλειδί στη ρύθμιση των υποδοχέων της LDL-C στην επιφάνεια του ηπατοκυττάρου και στον καθορισμό των επίπεδων της LDL χοληστερόλης που κυκλοφορεί στο πλάσμα Abifadel M, et al. Nat Genet. 2003;34: Lagace TA, et al. J Clin Invest. 2006;116:

62 LDL-R : διάρκεια ζωής 30 ώρες. 150 φορές λαμβάνει χώρα η διαδικασία να βάλει στο ηπατικό κύτταρο την προσλαμβανόμενη LDL-C και να βγεί πάλι στην επιφάνεια του κυττάρου. ( χρόνος όλης της διαδικασίας 12 λεπτά )

63 PCSK9 Regulates the Recycling of LDLR by Targeting the LDLR for Degradation Decreased LDLR surface concentration LDLR/PCSK9 routed to lysosome Monoclonal antibodies target PCSK9 and reduce the degradation of LDLR

64 Επισκόπηση των θεραπειών που στοχεύον την δράση της PCSK9 1-7 Εταιρεία Φάρμακο Παράγοντας Ένδειξη Φάση Inhibition of PCSK9 binding to LDL-R Sanofi/Regeneron Alirocumab Πλήρως ανθρώπινο mab Υπερχοληστερολαιμία Έγκριση ΕΜΑ Amgen Evolocumab Πλήρως ανθρώπινο mab Υπερχοληστερολαιμία Έγκριση EMA Pfizer/Rinat Neuroscience Bococizumab mab Υπερχοληστερολαιμία 3 Novartis LGT209 mab Υπερχοληστερολαιμία 2 Roche/ Genentech RG7652 mab Υπερχοληστερολαιμία 2 Eli-Lilly LY mab Υπερχοληστερολαιμία 2 PCSK9 protein binding fragment BMS/Adnexus BMS Adnexins Υπερχοληστερολαιμία 1 Inhibition of PCSK9 synthesis (gene silencing) Alnylam ALN-PCS02 sirna oligonucleotides Υπερχοληστερολαιμία 2 Idera TBD Antisense oligonucleotide Υπερχοληστερολαιμία Προκλινική Inhibition of PCSK9 autocatalytic processing Seometrix SX-PCK9 Small peptide mimetic Υπερχοληστερολαιμία Προκλινική Shifa Biomedical TBD Small molecule Μεταβολικές διαταραχές Προκλινική Cadila Healthcare TBD Small molecule Προκλινική 1. Rhainds D, et al. Clin Lipidol 2012;7: Lambert G, et al. J Lipid Res. 2012;53: Clinicaltrials.gov. RUTHERFORD-2, NCT Clinicaltrials.gov. SPIRE-HR, NCT Nature Reviews: Drug Discovery. Selected PCSK9-targeted agents in development. Available at: Accessed Feb Clinicaltrials.gov. LY , NCT Stein EA, Swergold GR. Curr Atheroscler Rep. 2013:15:310. mab 64 = μονοκλωνικό αντίσωμα, sirna = σύντομης παρεμβολής RNA. Gene silencing,στοχεύει την λειτουργία του PCSK9 τόσο ενδο όσο και εξωκκυτταρίως,ενώ τα μιμητικά πεπτίδια κ τα μονοκλονικά αντισώματα αποκλειστικά στοχεύουν στο εξωκυττάριο PCSK9 και στην εξωκυττάρια δράση του

65 PCSK9 Inhibitors. Alirocumab was approved by the FDA on July 24, 2015 EMA :July 24, mg subcutaneously Q2W and may be increased to 150mg Evolocumab was approved by FDA on August 27, EMA: July 21, mg subcutaneously Q2W or 420 mg QM ( HoFH or 420 mg Q2W). Am Health Drug Benefits. 2015;8(8):

66 Evolocumab Alirocumab Πλήρως ανθρώπινο μονοκλωνικό αντίσωμα της PCSK9 Λιγότερο πιθανό να εμφανίσει ανεπιθύμητες ενέργειες του ανοσοποιητικού: Ουδετεροπενία Θρομβοπενία Αιμολυτική αναιμία Αντιδράσεις υπερευαισθησίας

67 NEJM 2015

68 prespecified but exploratory analysis NEJM 2015

69 Alirocumab Maintained Consistent LDL-C Reductions NEJM 2015

70 EFFICACY: Major Adverse Coronary Events Robinson JG et al. NEJM 2015; Mar 15 NEJM 2015

71 Ανεπιθύμητες Ενέργειες Σύνοψη Αριθμός ασθενών (%) Alirocumab (N=1550) Εικονικό φάρμακο (N=788) Τιμή-p Οποιαδήποτε ανεπιθύμητη ενέργεια 1255 (81,0) 650 (82,5) 0,40 Σοβαρή ανεπιθύμητη ενέργεια 290 (18,7) 154 (19,5) 0,66 Ανεπιθύμητη ενέργεια που οδήγησε στη διακοπή λήψης του φαρμάκου της μελέτης Ανεπιθύμητη ενέργεια που οδήγησε σε θάνατο 111 (7,2) 46 (5,8) 0,26 8 (0,5) 10 (1,3) 0,08 Μέση έκθεση στο φάρμακο της μελέτης 1550 ασθενών που έλαβαν θεραπεία με Alirocumab και 788 ασθενών που έλαβαν θεραπεία με εικονικό φάρμακο: 70 εβδομάδες 2061 ασθενείς-έτη έκθεσης στο Alirocumab σε δόση των 150 mg Q2W Robinson JG et al. NEJM 2015, 372:

72 Εγκέφαλος και PCSK9. Η σχέση του PCSK9 με την αγγειακή άνοια και την νόσο Alzheimer είναι αμφιλεγόμενη. PCSK9 λαμβάνει μέρος: α στην αποδόμηση του b-site amyloid precursor protein - cleaving enzyme 1 (BASE1),που διασπά την πρόδρομη πρωτείνη του αμυλοειδούς (APP), και έτσι στη μη παραγωγή του amyloid β peptide και β. στην παραγωγή του amyloid β peptide J Lipid Res.2013; 54:

73 Conclusions In the past and present Statins CVD disease (<70) very risk (diabetes) (<100) moderate risk (<115), PAD, CKD may be consider after transplantation and chemotherapy Statins and ezetimibe increased the survival and reduced side effects of statins FUTURE PCSK9