Statines en LDL-Cholesterol Hypothese

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2 Statines en LDL-Cholesterol Hypothese Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2): LaRosa JC et al. N Engl J Med 2005;352:

3 Belang van LDL-Cholesterol Lineaire Associatie tussen Genetische en Farmacologische gemedieerde laag LDL-C en CV Risico Proportional reduction in CHD risk (log scale) 30% 20% 10% PCSK9 rs NPC1L1 rs ABCG5/8 rs HMGCR rs12916 LDLR rs PCSK9 rs Genetically lower LDL-C NPC1L1 LDL-C score HMGCR LDL-C score HMGCR LDL-C score NPC1L1 LDL-C score LDLR rs Combined NPC1L1 & HMGCR LDL-C score A to Z GISSI-P SEARCH PCSK9 46L rs Pharmacologically lower LDL-C IMPROVE-IT 69.5% reduction in CHD risk for each 38 mg/dl lower LDL-C ALLHAT-LLT ~20% reduction in CHD risk for each 38 mg/dl lower LDL-C Lower LDL-C (mg/dl) Ference BA, et al. J Am Coll Cardiol 2015;65:

4 Belang van LDL-Cholesterol Elke verlaging van de LDL-C waarde met 1 mmol/l (40 mg/dl) vermindert het jaarlijkse risico op CV events met ongeveer 20-24%, onafhankelijk van het werkingsmechanisme 1,2,3,4 Relative Risk Reduction 1. Cholesterol Treatment Trialists (CTT) Collaborators. Lancet. 2010;376: Perk J, et al. Eur Heart J. 2012;33(13): Cannon CP, et al. N Engl J Med 2015;372: CTT Collaboration. Lancet 2005;366: LDL-C reduction (mmol/l)

5 Familiale Hypercholesterolemie Prevalentie van HeFH is ~1: Prevalentie van HoFH is ~1:1,000,000 2,3 Frequency per 1000 births 2,5 2,0 1,5 1,0 0,5 2.0 per ,0 FH Dominant otosclerosis Adult PCKD Sickle cell disease Multiple Huntington's exostoses disease Fragile X syndrome Neurofibromatosis Cystic fibrosis Duchenne muscular dystrophy PCKD, polycystic kidney disease. Figure adapted from Genetic Alliance UK. Available at 1. Citkowitz E. Familial Hypercholesterolemia Vella A, et al. Mayo Clin Proc. 2001;76(10): Austin MA, et al. Am J Epidemiol. 2004;160(5):

6 HeFH versus HoFH FH is een autosomaal dominante genetische aandoening HeFH Veroorzaakt door 1 defect gen LDL-C waarden: mg/dl Risico op vroegtijdig CVD 20x verhoogd Vroegtijdig atherosclerotisch CVD jaar bij mannen jaar bij vrouwen Geschatte prevalentie 1:500 (oude schatting) tot 1:200 België: > patiënten Europa: 4,5 M patiënten HoFH Veroorzaakt door 2 defecte genen LDL-C waarden: mg/dl Verspreid atherosclerotisch CVD Eerste CVD vaak tijdens kinderjaren CV sterfte < 20 jaar Zeer zelden Geschatte prevalentie 1: (oude schatting) tot 1: één copy (allel) van het gen is defect beide copies (allelen) van het gen zijn defect

7 Cholesterol Values in Context General Population Courtesy Prof. Ernst Rietzschel, UZ Gent SABE.ALI

8 Cholesterol Values in Context Homozygous FH Population (HoFH) Courtesy Prof. Ernst Rietzschel, UZ Gent SABE.ALI

9 Distribution of LDL-C Levels According to Mutation Status Khera et al JACC 2016 SABE.ALI

10 FH - Most Common Mutations Image reproduced from 1. De Castro-Oros I, et al. Appl Clin Genet. 2010;3: SABE.ALI

11 Consequences of FH Mutations (2) People exposed to very high cholesterol from birth, reaching a threshold for CVD early in life Adapted from Horton et al. J Lipid Res 2009;50:S172-S177 SABE.ALI

12 Diagnosis of FH in Adults DLCN (Dutch Lipid Clinic Network) Score Nordestgaard et al. Eur Heart J 2013;34: doi: /eurheartj/eht273 Wiegman et al. Eur Heart J 2015;36: doi: /eurheartj/ehv157 SABE.ALI

13 Baseline (untreated) LDL-C Values Needed for the DLCN Score! SABE.ALI

14 SABE.ALI FH Treatment

15 ESC Guidelines voor Familiale Hypercholesterolemie Alle FH patiënten in hoog risico categorie LDL-cholesterol targets 1 Kinderen: LDL-C < 135 mg/dl (start LLT vanaf 8 j 2 ) Volwassenen: LDL-C < 100 mg/dl (zonder doorgemaakt CVD) LDL-C target < 70 mg/dl (met doorgemaakte CVD) 1. Nordestgaard et al. Eur Heart J 2013; 34: Wiegman et al. FH consensus in children, Eur Heart J, 2015,

16 Huidige behandelingsmogelijkheden GEMIDDELDE LDL-C DALING Intensiteit: 1. Statines Standaardbehandeling 2. Ezetimibe Als bijkomende LDL-daling nodig is of bij statine-intolerantie Laag Matig Hoog fluva 40 prava simva 10 <30% atorva fluva 80 prava rosu 5-10 simva atorva rosu % tot 22% 30% tot <50% 50% Stone N et al. JACC 2014;25(63) : Reiner Z et al. Eur Heart J. 2011;32:

17 Verdubbelen van statinedosis: 6 % additionele LDL-C reductie

18 FH Warrants Early Treatment accumulated LDL-C level accumulated LDL-C level Courtesy Prof. Ernst Rietzschel, UZ Gent SABE.ALI

19 FH Treatment Steps Courtesy Prof. Ernst Rietzschel, UZ Gent SABE.ALI

20 Statins and Muscle Pain Courtesy Prof. Ernst Rietzschel, UZ Gent SABE.ALI

21 LDL-C below the recommended target is very difficult in FH patients Only a small proportion of patients achieves the LDL-C < 100mg/dl goal 15% LDL-C > 160 mg/dl 21% 160 mg/dl 100 mg/dl Pijlman et al. Atherosclerosis 2010; 209: SABE.ALI

22 Evolutie van mabs Murien (0% humaan) Chimeer (65% humaan) Gehumaniseerd (> 90% humaan) Volledig humaan (100% humaan) Suffix -omab -ximab -zumab -umab Sterk Potentiële immunogeniciteit Zwak Monoklonale antilichamen tegen PCSK9: Alirocumab Praluent Sanofi Evolocumab Repatha Amgen

23 Anti-PCSK9 Moncolonal Antibodies Block LDL-R/PCSK9 Interaction and Lower LDL-C Levels For illustration purposes only 1. Adapted from Ferdinant et al ; Cardiovasc Drugs Ther;2015 SABE.ALI

24 Praluent ODYSSEY Long TermTrial: Efficacy Consistent LDL-C Reduction over 78 Weeks 1 Robinson JG et al. NEJM 2015; 372: SABE.ALI

25 Het veiligheidsprofiel van alirocumab is vergelijkbaar met placebo PRALUENT (alirocumab) Injection (N=1550) PRALUENT 2 Consecutive LDL-C <25 mg/dl (N=575) Placebo (N=788) AE leading to study d/c 7.2% 4.5% 5.8% AE leading to death 0.5% 0.7% 1.3% AEs Occurring in 5% of Any Group Nasopharyngitis 13.5% 11.0% 13.1% URTI 7.4% 6.1% 8.6% Injection site reaction 5.9% 3.8% 4.2% Urinary tract infection 5.8% 6.1% 6.9% Diarrhea 5.8% 4.9% 5.7% Influenza 5.7% 4.5% 5.7% Back pain 5.5% 6.1% 6.7% Myalgia 5.4% 3.1% 2.9% Bronchitis 5.4% 5.4% 5.2% Arthralgia 5.3% 3.8% 6.6% Headache 5.0% 1.9% 5.7% AE=adverse event; d/c=discontinuation; LDL-C= low-density lipoprotein cholesterol; URTI=upper respiratory tract infection. Adapted from Robinson JG, et al. N Engl J Med. 2015;372(16): (supplementary appendix). (gegevens uit Odyssey Long Term)

26 Gebruik en Huidig toepassingsgebied (terugbetaling) in België SABE.ALI

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