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
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
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. 310. http://who.int/mediacentre/factsheets/fs310/en/index.html. Accessed July 2014. 2. Go AS, et al. Circulation. 2013;127:e6 e245. 3. Nichols M, et al. European Cardiovascular Disease Statistics. 4th ed. Brussels, Belgium: European Heart Network; 2012. 4. World Health Organization Media Centre. http://www.who.int/mediacentre/factsheets/fs317/en/index.html. Accessed February 12 2014. 5. Mathers CD, Loncar D. PLoS Med. 2006;3(11):e442. doi:10. 1371/journal.pmed.0030442. CVD, cardiovascular disease.
15,152 cases and 14,820 controls from 52 Countries
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 256 128 64 32 16 8 4 2 1 Age at risk (years) 80 89 70 79 60 69 50 59 40 49 0.5 4.0 5.0 6.0 7.0 8.0 (mmol/l) 155 193 232 270 309(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;370:1829 1839. 2. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010;376:1670 1681. 3. Ridker PM, et al. for the JUPITER Study Group. N Engl J Med. 2008;359:2195 2207. 4. National Institute for Health and Care Excellence (2008). Identification and management of familial hypercholesterolaemia: NICE clinical guideline 71.
Age-adjusted CHD death rate/1000 men/6 years 18 16 14 12 10 8 6 4 2 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]) 0 140 180 220 260 160 200 240 280 Serum cholesterol mg/dl 300 1. Martin MJ, et al. Lancet. 1986;2(8513):933 6. CHD, coronary heart disease; MRFIT, Multiple Risk Factor Intervention Trial for the Prevention of CHD.
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 2.85 1.80 1.15 Adjusted for age and race 10-year follow-up Women n=6907 Men n=5432 0.75 80 100 120 140 160 180 LDL-C (mg/dl). Sharrett AR, et al. Circulation. 2001;104(10):1108 13. RIC, Atherosclerosis Risk In Communities; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol
Τα χαµηλά επίπεδα γέννησης LDL-C αυξάνονται µε το θηλασµό και την ενήλικη ζωή µε έκθεση στη δυτική διατροφή 140 120 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) 100 80 60 40 Plasma TC (mg/dl) 20 0 33-34 41-42 4 5 ff*4 5 bf* 20 39 40 59 60 74 Weeks in utero (n=79) Months (n=18) Years (n=8,174) Data from a variety of sources, see 2. 1. LaRosa JC, et al. Am J Cardiol. 2012;111:1221 1229. 2. Dietschy JM, Turley SD. J Lipid Res. 2004;45:1375 1397. *formula-fed breastfed TC, total cholesterol
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 0 70 90 110 130 150 170 190 210 O Keefe JH, et al. J Am Coll Cardiol. 2004;43(11):2142 2146. Mean total cholesterol (mg/dl)
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): 151-163
Αλγόριθµος φαρµακευτικής θεραπευτικής προσέγγισης ασθενών µε δυσλιπιδαιµία ΔΥΣΛΙΠΙΔΑΙΜΙΑ* Hellenic Journal of Atherosclerosis 2014;5(3): 151-163 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
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 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. 3337 (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. 2010 Nov 13; 376(9753): 1670 681.
Οι στατίνες αυξάνουν τον κίνδυνο νεοεµφανιζόµενου ΣΔΤ2 Κίνδυνος διαβήτη 9% σε 4 έτη (n = 91.140) n Στατίνη Εικ. φάρµ. ή µάρτυρας OR (95% CI) Βάρος (%) Ατορβαστατίνη ASCOT-LLA 7773 154 134 1,14 (0,89-1,46) 7,07% Σιµβαστατίνη HPS 1457 335 293 1,15 (0,98-1,35) 13,91% 4S 4242 3 198 193 1,03 (0,84-1,28) 8,88% Υποσύν. (I 2 =0,0%, p=0,445) 1,11 (0,97-1,26) 22,80% Ροσουβαστατίνη JUPITER 1780 270 216 1,26 (1,04-1,51) 11,32% 2 CORONA 3534 100 88 1,14 (0,84-1,55) 4,65% GISSI HF 3378 225 215 1,10 (0,89-1,35) 9,50% Υποσύν. (I 2 =0,0%, p=0,607) 1,18 (1,04-1,33) 25,46% Πραβαστατίνη WOSCOPS 5974 75 93 0,79 (0,58-1,10) 4,24% LIPID 6997 126 138 0,91 (0,71-1,17) 6,53% PROSPER 5023 165 127 1,32 (1,03-1,69) 6,94% MEGA 6086 172 164 1,07 (0,86-1,35) 8,03% ALLHAT-LLT 6087 238 212 1,15 (0,95-1,41) 10,23% GISSI PREVENZIONE 3460 96 105 0,89 (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 6211 72 74 0,98 (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: 735-42 Μειωµένος κίνδυνος διαβήτη Αυξηµένος κίνδυνος διαβήτη (1,02-1,17) 100%
EUROASPIRE IV Ασθενείς σε υπολιπιδαιµική θεραπεία 98%
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. 2016 Dec;23(18):2007-2018.
EUROASPIRE IV - Εκτός στόχων οι περισσότεροι από αυτούς που παίρνουν υπολιπιδαιµική θεραπεία < (70 mg/dl) Kotseva et al. Eur J Prev Cardiol. 2016 Dec;23(18):2007-2018.
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
LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp Simva 69.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dl -16.7-19.3-16.7 +0.6-0.5 Median Time avg 69.5 vs. 53.7 mg/dl
Primary Endpoint - ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke HR 0.936 CI (0.887, 0.988) p=0.016 Simva - 34.7% 2742 events NNT= 50 EZ/Simva - 32.7% 2572 events 6.4 % Treatment effect 7-year event rates
IMPROVE-IT: Primary endpoint on-treatment Event rate (%) 40 30 20 10 HR=0.924 CI: 0.868, 0.983 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 0 0 1 2 3 4 5 6 7 Time since randomization (years) 1. Cannon CP, et al. American Heart Association Scientific Sessions, Session LBCT.02 November 17, 2014, Chicago.
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
CTT µετα-ανάλυση Η µείωση του απόλυτου κινδύνου µε τις στατίνες εξαρτάται από: Cholesterol Treatment Trialists Collaboration (CTTC) n= 170 000 1. 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:10.1093/eurheartj/ehu228.
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?
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 12 20 10 8 Frequency (%) 0 0 1.3 2.6 3.9 5.2 6.5 7.8 PCSK9 142X or PCSK9 679X (n=85) 30 CHD (%) 4 20 10 0 0 1.3 2.6 3.9 5.2 6.5 7.8 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;354:1264 72. CHD, coronary heart disease.
PCSK9 way of action
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):18 28. 2. Soufi M, et al. Gene. 2013;521(1): 200 3. LDL, Low-density lipoprotein.
THEREFORE A GENETIC DISCOVERY INTO A NEW THERAPY A fully human monoclonal antibody against PCSK9 + blocks PCSK9/LDL-R interaction
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
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
LDL Cholesterol 100 Placebo LDL Cholesterol (mg/dl) 75 50 25 59% mean reduction (95%CI 58-60), P<0.00001 Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median LDL-C = 30 mg/dl) 0 0 12 24 36 49 61 73 85 97 109 121 134 146 158 170 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Weeks
Primary Endpoint CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 12% 8% 4% Hazard ratio 0.85 14.6% (95% CI, 0.79-0.92) P<0.0001 Placebo 12.6% Evolocumab ΝΝΤ = 74 0% 0 6 12 18 24 30 36 Months from Randomization
Key Secondary Endpoint CV Death, MI, or Stroke 10% 8% 5% 3% Hazard ratio 0.80 (95% CI, 0.73-0.88) P<0.00001 Placebo Evolocumab 9.9% 7.9% 0% 0 6 12 18 24 30 36 Months from Randomization
Landmark Analysis 8% 16% RRR 8% 25% RRR 6% HR 0.84 (95%CI 0.74-0.96) P=0.008 6% HR 0.75 (95%CI 0.66-0.85) P<0.00001 CV Death, MI, Stroke 4% Placebo 4% 2% 2% Evolocumab 0% 0% 0 3 6 9 12 12 18 24 30 36 Months from Randomization
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
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
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.
Summary of Statin Initiation Recommendations to Reduce ASCVD Risk (Revised Figure)
An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School
2016 European Lipid Guidelines
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
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-<100 100-<125 125-<150 150-<175 175** 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):485-494.
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 20 29 38 47 56 65. 74 83 92 101 110 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.
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):479-497.
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):479-497.
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 250 3 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;8:436-442; 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: 1981-2030; 3. Bouhairie VE, et al. Cardiol Clin. 2015;33:169-179; 4. Turgeon RD, et al. Can
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.
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