Β. Αθυρος, MD, FESC, FRSPH, FASA, FACS 2 η Πρ. Παθολογική Κλινική, Ιπποκράτειο Νοσοκοµείο, Αριστοτέλειο Πανεπιστήµιο Θεσσαλονίκης

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1 Στόχοι της υπολιπιδαιµικής αγωγής µετά τις νεώτερες µελέτες. Τι λένε και πως πρέπει να διαµορφωθούν οι κατευθυντήριες οδηγίες Β. Αθυρος, MD, FESC, FRSPH, FASA, FACS 2 η Πρ. Παθολογική Κλινική, Ιπποκράτειο Νοσοκοµείο, Αριστοτέλειο Πανεπιστήµιο Θεσσαλονίκης

2 Δήλωση σύγκρουσης συµφερόντων Οι παρουσιάσεις στοχεύουν σε εκπαιδευτικούς σκοπούς και µόνο και δεν αντικαθιστούν την ανεξάρτητη επιστηµονική κρίση Οι τοποθετήσεις ως προς τα δεδοµένα και οι απόψεις που εκφράζονται προέρχονται αποκλειστικά από τους οµιλητές ατοµικώς και, εκτός από την περίπτωση που δηλώνεται ρητά το αντίθετο δεν αποτελούν θέση των εταιρειών. Δεν χορηγείται τιµητική αµοιβή για τη συγκεκριµένη οµιλία Ο οµιλητής έχει λάβει τιµητική αµοιβή την τελευταία διετία από τις ακόλουθες εταιρείες: AMGEN, Sanofi, MSD

3 CVD is the number one cause of non-communicable death globally A summary of the leading causes of death globally; of the top 10 causes of death globally in 2012, CVD accounted for 28% of all deaths 1 The leading causes of death globally 1 Percent (%) of deaths 30,0 22,5 15,0 7,5 CVD (ischaemic heart disease, stroke and other cerebrovascular disease) Lower respiratory infections Chronic obstructive pulmonary disease Diarrhoeal disease HIV/AIDS Trachea, bronchus, lung cancers Tuberculosis Diabetes mellitus Road traffic accidents On average, one American dies from CVD every 40 seconds; equating to approximately 2,200 deaths each day 2 0,0 Each year, CVD causes over 4 million deaths in Europe and over 1.9 million deaths in the European Union 3 >80% of CVD deaths take place in low- and middle-income countries and occur almost equally in men and women 4 By 2030, almost 23.3 million people globally will die from CVD annually, mainly from heart disease and stroke 5 1. World Health Organization. Factsheet No Accessed July Go AS, et al. Circulation. 2013;127:e6 e Nichols M, et al. European Cardiovascular Disease Statistics. 4th ed. Brussels, Belgium: European Heart Network; World Health Organization Media Centre. Accessed February Mathers CD, Loncar D. PLoS Med. 2006;3(11):e442. doi: /journal.pmed CVD, cardiovascular disease.

4 15,152 cases and 14,820 controls from 52 Countries

5 The causal relationship between cholesterol levels and CV risk is well established A meta-analysis of 61 prospective observational studies of vascular mortality, comprising of nearly 900,000 healthy participants Blood pressure and total cholesterol was measured at baseline to determine the joint relevance of each of these risk factors 1 There is a continuous positive relationship between CV risk and serum total cholesterol concentrations 1 There is a strong positive relationship between LDL-C reduction with statins and the frequency of CVD events 2 This is also observed in apparently healthy individuals without hypercholesterolemia 3 Patients with heterozygous familial hypercholesterolemia (HeFH) have life-long exposure to very high LDL-C levels and typically develop CVD relatively early in life 4,5 Hazard Ratio (95% CI) Ischemic heart disease mortality vs total cholesterol Age at risk (years) (mmol/l) (mg/dL) The Lancet, 370, Prospective Studies Collaboration, Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths,. 1. Prospective Studies Collaboration. Lancet. 2007;370: Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010;376: Ridker PM, et al. for the JUPITER Study Group. N Engl J Med. 2008;359: National Institute for Health and Care Excellence (2008). Identification and management of familial hypercholesterolaemia: NICE clinical guideline 71.

6 Age-adjusted CHD death rate/1000 men/6 years MRFIT screening data: Association of serum cholesterol and CHD death in 361,662 men MRFIT was a large, multicentre cohort study of middle-aged men with high CV risk. Its aim was to determine the risk relationship between serum cholesterol and CHD, and to compare it with the pattern observed between blood pressure and CHD risk 20 th percentile CHD mortality increased progressively above the 20th percentile for serum cholesterol (>181 mg/dl [4.68 mmol/l]) Serum cholesterol mg/dl Martin MJ, et al. Lancet. 1986;2(8513): CHD, coronary heart disease; MRFIT, Multiple Risk Factor Intervention Trial for the Prevention of CHD.

7 ARIC Study: Relationship of LDL-C to CHD in men and women ARIC was a population-based sampling of 15,792 residents, 45 to 64 years old from 4 communities in NC, MS, MN, and MD 4.50 Relative Risk of CHD Adjusted for age and race 10-year follow-up Women n=6907 Men n= LDL-C (mg/dl). Sharrett AR, et al. Circulation. 2001;104(10): RIC, Atherosclerosis Risk In Communities; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol

8 Τα χαµηλά επίπεδα γέννησης LDL-C αυξάνονται µε το θηλασµό και την ενήλικη ζωή µε έκθεση στη δυτική διατροφή Newborn data from premature (n=38) and term (n=41) neonates; infant data based on a small series (n=18); adult data from NHANES III database 1 Mean LDL-C (mg/dl) Plasma TC (mg/dl) ff*4 5 bf* Weeks in utero (n=79) Months (n=18) Years (n=8,174) Data from a variety of sources, see LaRosa JC, et al. Am J Cardiol. 2012;111: Dietschy JM, Turley SD. J Lipid Res. 2004;45: *formula-fed breastfed TC, total cholesterol

9 Οι Δυτικοί άνθρωποι είναι τα µόνα θηλαστικά που έχουν ολική χοληστερόλη >160 mg/dl Field observations of hunter-gatherer populations showed them to be generally free of symptoms of CVD even when living beyond 70. These populations had total cholesterol levels of 100 to 150 mg/dl with estimated LDL cholesterol levels of approximately 50 to 75 mg/dl. Healthy, wild, adult primates show LDL-C levels of approximately 40 to 80 mg/dl. 1 Hunter-Gatherers: Haz da Inuit!Kung Pygmy San Wild Primates: Baboon Howler monkey Night monkey Wild Mammals: Horse Boar Peccary Black rhinoceros African Elephant Modern Humans: Adult American O Keefe JH, et al. J Am Coll Cardiol. 2004;43(11): Mean total cholesterol (mg/dl)

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11 ΘΕΡΑΠΕΥΤΙΚΟΙ ΣΤΟΧΟΙ ΤΗΣ LDL-C ΚΑΤΗΓΟΡΙΑ ΚΙΝΔΥΝΟΥ ΠΟΛΥ ΥΨΗΛΟΣ: ΚΑΝ, ΣΔ2, ΣΔ1 >40 ετών, µέτρια-σοβαρή ΧΝΝ, Hellenic Heart SCORE>10% LDL-C >50% και LDL-C <70 mg/dl ΥΨΗΛΟΣ: SCORE 5-10%, ή 1 πολύ επιβαρυντικός παράγοντα κινδύνου, Οικογ. υπερχοληστερολαιµία, αυτοάνοσα φλεγµονώδη LDL-C νοσήµατα <100 mg/dl ΜΕΤΡΙΟΣ-ΧΑΜΗΛΟΣ: SCORE <5% LDL-C <115 mg/dl Hellenic Journal of Atherosclerosis 2014;5(3):

12 Αλγόριθµος φαρµακευτικής θεραπευτικής προσέγγισης ασθενών µε δυσλιπιδαιµία ΔΥΣΛΙΠΙΔΑΙΜΙΑ* Hellenic Journal of Atherosclerosis 2014;5(3): ΣΤΑΤΙΝΗ + ΕΖΕΤΙΜΙΜΠΗ ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ ΤΗΣ ΣΤΑΤΙΝΗΣ*** ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ + ΚΟΛΕΣΕΒΕΛΑΜΗ ΣΤΑΤΙΝΗ** ΦΥΣΙΟΛΟΓΙΚΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ HDL CHOL CHOL ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ + ΦΑΙΝΟΦΙΜΠΡΑΤΗ ΥΨΗΛΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΧΑΜΗΛΗ HDL CHOL ΣΤΑΤΙΝΗ + ω-3 ΛΙΠΑΡΑ ΟΞΕΑ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL, ΤΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΤΗΝ HDL CHOL ΜΕΓΙΣΤΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΟΦΕΛΟΣ *Αν τριγλυκερίδια νηστείας >500 mg/dl συνιστάται η άµεση χορήγηση µίας φιµπράτης ή/και ω-3 λιπαρών οξέων **Για την επίτευξη του στόχου της αγωγής συνιστάται η χορήγηση µιας στατίνης σε δόση που αναµένεται να επιτύχει το στόχο της θεραπείας ***Κάθε διπλασιασµός της δόσης µίας στατίνης οδηγεί σε 6% περαιτέρω ελάττωση της LDL CHOL

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14 Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from participants in 26 randomised trials Μείζον αγγειακό επεισόδιο και προηγούµενος διαβήτης Μείζον στεφανιαίο επεισόδιο Επεισόδια (%) Θεραπεία Μάρτυρας RR (CI) Με διαβήτη 776 (8,3%) 979 (10,5%) 0,78 (0,69-0,87) Χωρίς διαβήτη 2561 (7,2%) 3441 (9,6%) 0,77 (0,73-0,81) Οποιοδήπ. µείζον στεφανιαίο επεισ (7,4%) 4420 (9,8%) 0,77 (0,74-0,80) Τεστ ετερογένειας εντός υποοµάδας =0,1, p=0,8 X 2 1 Επαναγγείωση στεφανιαίων Με διαβήτη 491 (5,2%) 627 (6,7%) 0,75 (0,64-0,88) Χωρίς διαβήτη 2129 (6,0%) 2807 (7,9%) 0,76 (0,72-0,81) Οποιαδ. επαναγγείωση στεφανιαίων 2620 (5,8%) 3434 (7,6%) 0,76 (0,73-0,80) Τεστ ετερογένειας εντός υποοµάδας =0,1, p=0,8 X 2 1 Εγκεφαλικό επεισόδιο Με διαβήτη 407 (4,4%) 501 (5,4%) 0,79 (0,67-0,93) Χωρίς διαβήτη 933 (2,7%) 1116 (3,2%) 0,84 (0,76-0,93) Οποιοδήποτε εγκεφαλικό επεισόδιο 1340 (3,0%) 1617 (3,7%) 0,83 (0,77-0,88) Τεστ ετερογένειας εντός υποοµάδας =0,8, p=0,4 X 2 1 Μείζον αγγειακό επεισόδιο Με διαβήτη 1465 (15,6%) 1782 (19,2%) 0,79 (0,72-0,93) Χωρίς διαβήτη 4889 (13,7%) 6212 (17,4%) 0,79 (0,76-0,82) Κάθε µείζον αγγειακό επεισόδιο 6354 (14,1%) 7994 (17,8%) 0,79 (0,77-0,81) Τεστ ετερογένειας εντός υποοµάδας X 2 1 =0,0, p=0,9 RR (99% CI) RR (95% CI) 0,5 1,0 1,5 Θεραπεία καλύτερη Μάρτυρας καλύτερος CTTC. Lancet Nov 13; 376(9753):

15 Οι στατίνες αυξάνουν τον κίνδυνο νεοεµφανιζόµενου ΣΔΤ2 Κίνδυνος διαβήτη 9% σε 4 έτη (n = ) n Στατίνη Εικ. φάρµ. ή µάρτυρας OR (95% CI) Βάρος (%) Ατορβαστατίνη ASCOT-LLA ,14 (0,89-1,46) 7,07% Σιµβαστατίνη HPS ,15 (0,98-1,35) 13,91% 4S ,03 (0,84-1,28) 8,88% Υποσύν. (I 2 =0,0%, p=0,445) 1,11 (0,97-1,26) 22,80% Ροσουβαστατίνη JUPITER ,26 (1,04-1,51) 11,32% 2 CORONA ,14 (0,84-1,55) 4,65% GISSI HF ,10 (0,89-1,35) 9,50% Υποσύν. (I 2 =0,0%, p=0,607) 1,18 (1,04-1,33) 25,46% Πραβαστατίνη WOSCOPS ,79 (0,58-1,10) 4,24% LIPID ,91 (0,71-1,17) 6,53% PROSPER ,32 (1,03-1,69) 6,94% MEGA ,07 (0,86-1,35) 8,03% ALLHAT-LLT ,15 (0,95-1,41) 10,23% GISSI PREVENZIONE ,89 (0,67-1,20) 4,94% Υποσύν. (I 2 =47,5%, p=0,090) 1,03 (0,90-1,19) 40,91% Λοβαστατίνη AFCAPS/TexCAPS ,98 (0,70-1,38) 3,76% Σύνολο (I 2 =11,2%) 1,09 0,5 1,0 2,0 4,0 8,0 Sattar et al. Lancet 2010; 375: Μειωµένος κίνδυνος διαβήτη Αυξηµένος κίνδυνος διαβήτη (1,02-1,17) 100%

16 EUROASPIRE IV Ασθενείς σε υπολιπιδαιµική θεραπεία 98%

17 EUROASPIRE IV - Εκτός στόχων οι µισοί από αυτούς που παίρνουν υπολιπιδαιµική θεραπεία 100 mg/dl ~ ½ ασθενείς εκτός στόχων Kotseva et al. Eur J Prev Cardiol Dec;23(18):

18 EUROASPIRE IV - Εκτός στόχων οι περισσότεροι από αυτούς που παίρνουν υπολιπιδαιµική θεραπεία < (70 mg/dl) Kotseva et al. Eur J Prev Cardiol Dec;23(18):

19 IMProved Reduction of Outcomes: Vytorin Efficacy International Trial A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome

20 LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp Simva EZ/Simva Δ in mg/dl Median Time avg 69.5 vs mg/dl

21 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 % 2742 events NNT= 50 EZ/Simva % 2572 events 6.4 % Treatment effect 7-year event rates

22 IMPROVE-IT: Primary endpoint on-treatment Event rate (%) HR=0.924 CI: 0.868, p=0.012 CV event rate Simvastatin KM 32.4% 2079 events Ezetimibe/Simvastatin KM 29.8% 1932 events 7.6% Treatment effect Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (> 30 days after randomization), or stroke Time since randomization (years) 1. Cannon CP, et al. American Heart Association Scientific Sessions, Session LBCT.02 November 17, 2014, Chicago.

23 CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 Simva 22.2% 1704 events EZ/Simva 20.4% 1544 events 10 % Treatment effect 7-year event rates

24 CTT µετα-ανάλυση Η µείωση του απόλυτου κινδύνου µε τις στατίνες εξαρτάται από: Cholesterol Treatment Trialists Collaboration (CTTC) n= Τη µείωση LDL σε mg/dl 2. Τις αρχικές συγκεντρώσει ς της LDL Η απόλυτη µείωση των επιτευχθέντων επιπέδων LDL-C είναι ο πρωταρχικός προγνωστικός δείκτης του µεγέθους του οφέλους της θεραπείας στη µείωση του κινδύνου Laufs U et al. Eur Heart J. 2014;doi: /eurheartj/ehu228.

25 New LDL-C target? Η LDL-C 70 mg/dl πήγε σε 52 mg/dl. Αυτό σηµαίνει ότι σε ασθενείς µε ΟΣΣ πρέπει να Βάλουµε στόχο LDL-C το 53 mg/dl?

26 Loss-of-function mutations in PCSK9 are associated with lower serum LDL-C and lower incidence of CHD This was a large prospective study investigating the incidence of CAD over 15 years in the Atherosclerosis Risk in Communities study, in relation to the presence of PCSK9 LoF mutations 30 No mutation (n=3278) 50 th percentile Frequency (%) PCSK9 142X or PCSK9 679X (n=85) 30 CHD (%) Plasma LDL-C in black subjects (mmol/l) 0 No Yes PCSK9 142X or PCSK9 679X PCSK9 mutations were associated with a 28% reduction in mean LDL-C and an 88% reduction in the lifetime risk of CHD (p=0.008 for the reduction; HR=0.11; 95% CI: 0.02, 0.81; p=0.03) 1. Cohen JC, et al. N Engl J Med 2006;354: CHD, coronary heart disease.

27 PCSK9 way of action

28 PCSK9 mutations and effect on LDL metabolism Gain of Function LDL-R levels LDL clearance Loss of Function LDL-R levels LDL clearance LDL High risk for atherosclerosis and coronary heart disease (CHD) LDL Protection from atherosclerosis and CHD Adapted from 1. Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1): Soufi M, et al. Gene. 2013;521(1): LDL, Low-density lipoprotein.

29 THEREFORE A GENETIC DISCOVERY INTO A NEW THERAPY A fully human monoclonal antibody against PCSK9 + blocks PCSK9/LDL-R interaction

30 FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk MS Sabatine, RP Giugliano, AC Keech, N Honarpour, SM Wasserman, PS Sever, and TR Pedersen, for the FOURIER Steering Committee & Investigators American College of Cardiology 66 th Annual Scientific Session Late-Breaking Clinical Trial March 17, 2017

31 Global Enrollment 27,564 patients randomized at 1242 sites in 49 countries between 2/2013 6/2015 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

32 LDL Cholesterol 100 Placebo LDL Cholesterol (mg/dl) % mean reduction (95%CI 58-60), P< Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median LDL-C = 30 mg/dl) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Weeks

33 Primary Endpoint CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 12% 8% 4% Hazard ratio % (95% CI, ) P< Placebo 12.6% Evolocumab ΝΝΤ = 74 0% Months from Randomization

34 Key Secondary Endpoint CV Death, MI, or Stroke 10% 8% 5% 3% Hazard ratio 0.80 (95% CI, ) P< Placebo Evolocumab 9.9% 7.9% 0% Months from Randomization

35 Landmark Analysis 8% 16% RRR 8% 25% RRR 6% HR 0.84 (95%CI ) P= % HR 0.75 (95%CI ) P< CV Death, MI, Stroke 4% Placebo 4% 2% 2% Evolocumab 0% 0% Months from Randomization

36 New LDL-C target? Η LDL-C 90 mg/dl πήγε σε 30 mg/dl. Αυτό σηµαίνει ότι σε ασθενείς µε ΟΣΣ, FH, ΧΣΣΝ πρέπει να βάλουµε στόχο LDL-C το < 30 mg/dl? An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

37 Conclusions In patients with known cardiovascular disease: 1. PCSK9 inhibition with evolocumab significantly & safely major cardiovascular events when added to statin therapy 2. Benefit was achieved with lowering LDL cholesterol well below current targets An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

38 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women with Heart Disease American College of Cardiology Foundation and American Heart Association, Inc.

39 Summary of Statin Initiation Recommendations to Reduce ASCVD Risk (Revised Figure)

40 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

41 2016 European Lipid Guidelines

42 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease Writing Committee Chair: Paul S. Jellinger, MD, MACE Co-Chair: Yehuda Handelsman, MD, FACP, FACE Members: David S. H. Bell, MD, FACP, FACE Zachary T. Bloomgarden, MD, MACE Eliot A. Brinton, MD, FAHA, FNLA Michael H. Davidson, MD, FACC, FACP, FNLA Sergio Fazio, MD, PhD Vivian A. Fonseca, MD, FACE Alan J. Garber, MD, PhD, FACE George Grunberger, MD, FACP, FACE Chris K. Guerin, MD, FNLA, FACE Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU Rachel Pessah-Pollack, MD, FACE Paul D. Rosenblit, MD, PhD, FNLA, FACE Donald A. Smith, MD, MPH, FACE Kathleen Wyne, MD, PhD, FNLA, FACE Reviewers: Michael Bush, MD Farhad Zangeneh, MD

43 Meta-analysis of 8 Statin Trials (Moderate- to High- Intensity Dosing): Patients Who Achieved Very Low LDL-C Levels Had Lower Risk for Major Cardiovascular Events 1,0000 Adjusted* Hazard Ratio for Major CV Events *adjusted for sex, age, smoking, diabetes, SBP, HDL-C, and trial 0,7500 0,5000 0,2500 ** >200 mg/dl for non-hdl-c Very low LDL-C levels, lowest risk 0,4400 0,5900 Current very high risk goals 0,5500 0,5100 Current high risk goals 0,5900 0,6000 0,5600 N=40,000 0,6400 0,6400 0,5800 0,7100 0,6900 0,6400 0,9100 0,7500 0,7100 LDL-C Apo B Non-HDL-C 1,0000 1,0000 1,0000 0,0000 <50 50-<75 75-< < < < ** Cutoffs: LDL-C, ApoB, non-hdl-c Achieved On-Trial Atherogenic Cholesterol and Lipoprotein Concentration, mg/dl Abbreviations: apo, apolipoprotein; CV, cerebrovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5):

44 GLAGOV: Mean On-Treatment LDL-C vs. Change in Percent Atheroma Volume The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment 5/2013 to 1/2015) conducted at 197 academic and community hospitals in 6 continents, enrolling 968 patients (mean age 59.8 years, 27.8% female) with CAD 0,5 0,0 Curve truncated at 20 and 110 mg/dl owing to the small number of values outside that range Main 95% confidence level 95 % confidence level2 Patients with angiographic CAD were randomized to receive monthly evolocumab (420 mg) (n=484) or placebo (n=484) SQ for 76 weeks, in addition to statins Change In Percent Atheroma Volume (%) -0,5-1,0-1,5!plaque regression Locally weighted polynomial regression (LOESS) plot demonstrates a linear continuous relationship between achieved LDL-C level and PAV progression/ regression for levels of LDL- C ranging from 110 mg/dl to as low as 20 mg/dl Achieved On-Treatment LDL-C (mg/dl) Abbreviations: CAD, coronary artery disease; GLAGOV, Global Assessment of Plaque Regression With a PCSK9 Antibody ;LDL-C, low-density lipoprotein cholesterol; SQ, subcutaneous.

45 Question: What are lipid treatment goals? R35. Treatment goals for dyslipidemia should be personalized according to levels of risk (Grade A; BEL 1). ons associ ated with this quest ion: R36. For individuals at low risk (i.e., with no risk factors), an LDL-C goal of less than 130 mg/dl is recommended (Grade A; BEL 1). R37. For individuals at moderate risk (i.e., with 2 or fewer risk factors and a calculated 10-year risk of less than 10%), an LDL-C goal of less than 100 mg/dl is recommended (Grade A; BEL 1). R38. For individuals at high risk (i.e., with an ASCVD equivalent including diabetes or stage 3 or 4 CKD with no other risk factors, or individuals with 2 or more risk factors and a 10-year risk of 10%-20%), an LDL-C goal of less than 100 mg/dl is recommended (Grade A; BEL 1). Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; LDL-C, low-density lipoprotein cholesterol. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):

46 Question: What are lipid treatment goals? R39. For individuals at very high risk (i.e., with established or recent hospitalization for ACS; coronary, carotid or peripheral vascular disease; diabetes or stage 3 or 4 CKD with 1 or more risk factors; a calculated 10-year risk greater than 20%; or HeFH), an LDL-C goal of less than 70 mg/dl is recommended (Grade A; BEL 1). R40. For individuals at extreme risk (i.e., with progressive ASCVD, including unstable angina that persists after achieving an LDL-C less ons associ ated with this quest ion: than 70 mg/dl, or established clinical ASCVD in individuals with diabetes, stage 3 or 4 CKD, and/or HeFH, or in individuals with a history of premature ASCVD (<55 years of age for males or <65 years of age for females), an LDL-C goal of less than 55 mg/dl is recommended (Grade A; BEL 1). R41. An LDL-C goal of <100 mg/dl is considered acceptable for children and adolescents, with 100 to 129 mg/dl considered borderline and 130 mg/dl or greater considered high (based on recommendations from the American Academy of Pediatrics) (Grade D). Abbreviations: ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; HeFH. heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):

47 Familial Hypercholesterolemia: Prevalence and Risk FH is caused by genetic mutations passed on by: One parent (heterozygous, HeFH) 1 ons associ ated with this quest ion: Both parents (homozygous, HoFH) 1 HoFH prevalence ranges from 1 in 160,000 to 1 in 250,000 2,3 Individuals with HoFH have extremely high LDL-C levels (>500 mg/dl) and premature CV risk 4 Many with HoFH experience their first coronary event in childhood or adolescence 4 HeFH prevalence ranges from 1 in 200 to 1 in Individuals with HeFH can present with LDL-C levels 90 to 500 mg/ dl and have premature CV risk 4 On average, individuals with HeFH experience their first coronary event at age 42 (about 20 years younger than the general population) 4 Early treatment is recommended for all individuals with FH, with a 1. Zimmerman MP. goal Am Health of reducing Drug Benefits. LDL-C 2015;8: ; levels by 2. 50% Goldstein from J, baseline et al. The 3 Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995: ; 3. Bouhairie VE, et al. Cardiol Clin. 2015;33: ; 4. Turgeon RD, et al. Can

48 Συµπεράσµατα Η χαµηλή LDL-C ελαττώνει σηµαντικά τα ΚΑ συµβάµατα Πόσο πρέπει να είναι ο στόχος της LDL-C στις επόµενες οδηγίες? Οι Αµερικάνικοί πρέπει να καθορίσουν οριστικά συγκεκριµένους στόχους επιπλέον των ποσοστιαίων µειώσεων. Η χρήση της εζετιµίµπης εισφέρει κλινικό όφελος και είναι φθηνή. Οι αναστολείς PCSK9 προσφέρουν σηµαντικό κλινικό όφελος, επιπλέον της στατίνης-εζετιµίµπης, αλλά είναι ακόµη ακριβοί και πρέπει να χρησιµοποιούνται σε συγκεκριµένους ασθενείς. Η σχέση κόστους αποτελεσµατικότητας θα πρέπει να καθορίσει τα κάτω όρια της LDL-C που θα µπορούσε να είναι 40 mg/dl για ασθενείς µε πάρα πολύ υψηλό ΚΑ κίνδυνο.

49 Future Guidelines (????). Updated LDL-C Goals, Treatment Cut points Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0 1 risk factor <115mg/dL 115 mg/dl 130 mg/dl Moderately high risk: 2 risk factors <100 mg/dl 100 mg/dl 130 mg/dl High risk: SCHD or CHD risk equivalents * <70 mg/dl 90 mg/dl 90 mg/dl Very High risk: ACS + DM + CKD or <50 mg/dl 70 mg/dl 70 mg/dl