Familial Hypercholesterolemia: untreated and undiagnosed?

Transcription

1 Familial Hypercholesterolemia: untreated and undiagnosed? G.K. Hovingh MD PhD Department of Vascular Medicine AMC Amsterdam The Netherlands With the kind support of AMGEN

2 Disclaimer Dr. Kees Hovingh is consultant and speaker for biotech as well as pharmaceutical companies that develop molecules that influence lipoprotein metabolism, including Regeneron, Pfizer, MSD, Sanofi, Amgen, Roche and Genzyme Kees Hovingh is head of the Clinical trial unit AMC, and PI for clinical trials in dyslipidemia conducted with i.e. Amgen, Sanofi, Lilly, Novartis, Kowa, Genzyme, Cerenis, Pfizer, Astra

3 Greece - the Netherlands

4 Greece - the Netherlands v v inhabitants 16,856,620 10,816,286 area (km2) 41, ,957 FH pts (1:500) 34,000 21,000 cardiologists 994

5 Block Eur H J 2000;1135

6 FH NO BORDER S

7 Take Home Messages FH underdiagnosed and undertreated FH screening; how? and why? FH treatment: we should do better! Kids: treat early...

8 Looking back...

9 FH; the historical perspective Carl Muller Acta Medica Scan Vol 95;S89:

10 6 Endo 1976 Discovery of statins Discovery LDL receptor Brown and Goldstein 1974 Statins raise LDL receptors in the liver Plasma LDL-C reduction

11 Cholesterol: target? Br Med J 1992;305:15

12 FH; the transition from old concepts....hofh is an extremely rare (1: ) non -curable disease, chracterized by uniform clinical stigmata, leading to premature cardiovascular disease. HeFH ; 1: JIM 2003;239;2

13 to new insights....(ho)fh and hefh is a not-so-rare disease, which encompasses a broad spectrum of clinical phenotypes. We can t cure (yet), but we can redirect the phenotype... Sjouke et al Eur H J 2014;7

14 Nordestgaard, et Eur H J 2013:34(45):3478

15 Underdiagnosed? Most frequent autosomal dominant disorder in man Nordestgaard, et Eur H J 2013:34(45):3478

16 Diagnosis Group 1: Family history Points a) First degree relative with known premature (<55 years men; <60 years 1 women) coronary heart disease (CHD) OR b) First degree relative with known LDL cholesterol >95 th percentile by age and 1 gender for country c) First degree relative with tendon xanthoma and/or corneal arcus OR 2 d) Child(ren) <18 years with LDL cholesterol >95 th percentile by age and gender 2 for country Group 2: Clinical history a) Subject has premature (<55 years men; <60 years women) CHD b) Subject has premature (<55 years men; <60 years women) cerebral or peripheral vascular disease Group 3: Physical examination a) Tendon xanthoma b) Corneal arcus in a person <45 years Group 4: Biochemical results (LDL cholesterol) >8.5 mmol/l (>325 mg/dl) mmol/l ( mg/dl) mmol/l ( mg/dl) mmol/l ( mg/dl) Group 5: Genetic testing (DNA analysis) a) Causative mutation shown in the LDLR, APOB or PCSK9 genes 8 definite >/=8, probable 6/7 pts, possible 3-5, unlikely 0-2 Nordestgaard, et Eur H J 2013:34(45):

17 Prevalence: Is 1/500 for hefh and 1/ for HoFH correct?

18 Familial Hypercholesterolemia in the Netherlands 16.8 x 10 6 inhabitants prevalence hefh1:500, hofh: 1 in every 1x 10 6 WHO; FH report 1999 WHO/HGN/FH/CONS/99.2

19 Familial Hypercholesterolemia in the Netherlands 16.8 x 10 6 inhabitants prevalence hefh1:500, hofh: 1 in every 1x 10 6

20 Methods Patients in database DNA diagnostics laboratory AMC, Amsterdam N = 104,682 Double ADH mutation carriers N = 207 Excluded patients n = 157 Non-pathogenic mutation n = 94 Two mutations single allele n = 27 Double heterozygotes n = 25 Reside outside NL n = 9 Died n = 2 N = 50 Collection medical records Sjouke et al, Eur H J 2014

21 HoADH in the Netherlands 21 HoFH 25 Compound HeFH 4 HoFDB patients Ho/CompHeFH (LDLR) HoFDB (APOB) Sjouke et al, Eur H J 2014

22 LDL-C levels in HoADH Sjouke et al, Eur H J 2014

23 hoadh Conclusions High prevalence of HoADH ~1 : Large variability in phenotypes Phenotypic criteria HoADH underestimate number HoADH patients Number of headh: app 1:250 Sjouke et al, Eur H J 2014

24 1:200!!!! Familial Hypercholesterolemia;1:500??? the Copenhagen General Population Study, n=69000 Benn, Tybjærg-Hansen, Watts, and Nordestgaard JCEM 2012;97:

25 Underdiagnosed 1/250 35% Nordestgaard et al Eur H J 2014

26 How to identify FH patients?

27 Familial Hypercholesterolemia Requirements for Active Patient Identification Molecular Diagnosis Genetic Fieldwork Centers for Referral Database

28 R.Huijgen e.a Neth Heart Journal 2011

29 Familial Hypercholesterolemia Cascade screening Versmissen J et al BMJ 2009

30 Familial Hypercholesterolemia: Survival in Children Kusters DM et al JAMA 2014

31 Treatment

32 DUTCH EXPERIENCE: FH undertreated Pijlman et al Athersoclerosis 2009

33 DUTCH EXPERIENCE: FH undertreated

34 Familial Hypercholesterolemia Treatment the Copenhagen General Population Study, n=69000 Benn, Tybjærg-Hansen, Watts, and Nordestgaard JCEM 2012;97:

35 FH pts on Rx; did they reach the LDL-C goal?? No! Benn, Tybjærg-Hansen, Watts, and Nordestgaard JCEM 2012;97:

36 Statins: a short list of trials CHD - STABLE High cholesterol 4S Normal chol. CARE/LIPID/ALLIANCE Low vs High Rx TNT/SEARCH/IDEAL Real world GREACE CHD ACS Normal chol MIRACL PTCA AVERT CHD - CABG Normal chol Post CABG NO CHD High chol WOSCOPS Normal chol AFCAPS/TEXCAPS NO CHD + RISK FACTOR Hypertension ASCOT/ ALLHAT Diabetes CARDS CHD - ACS Low vs High dose PROVE-IT; A-Z pre PTCA ARMYDA- Recap/NAPLES II STROKE Normal chol SPARCL NO CHD high CRP JUPITER IMAGING FH ASAP/ ENHANCE no CHD METEOR Stable CHD REVERSAL/ASTEROID/SANDS Children LIPIDS/ZinK SPECIAL GROUPS high risk HPS Elderly PROSPER Asian population J-LIT/MEGA Renal Disease 4D/AURORA CTT, Lancet 2008;12;371(9607):117-25

37 Statins; CTT Meta-analysis in people CTT, Lancet 2008;12;371(9607):117-25

38 Statins; CTT Meta-analysis in people We all benefit! CTT, Lancet 2008

39 Today s Reality Reduction MACE statin vs placebo (%) CTT, Lancet 2008

40 Today s Reality Reduction MACE statin vs placebo (%) 0-30 Potential for further risk reduction -100 CTT, Lancet 2008

41 Reduction MACE statin +?? vs placebo (%) 0 Potential for further risk reduction = other lipid altering strategies?

42 Lipid Modifying Drugs Cholesterol absorption inhibitors Squalene synthase inhibitors (SSI) Microsomal triglyceride transfer protein (MTP) inhibitors Acyl coenzyme A acyltransferase (ACAT) inhibitors Diacylglycerol acyltransferase (DGAT) inhibitors Thyroxin receptor agonists ApoB mrna antisense drugs PCSK9 antibodies ApoA1-based strategies (iv) Cholesterol ester transfer protein (CETP) inhibitors

43 Lipid Modifying Drugs Cholesterol absorption inhibitors Squalene synthase inhibitors (SSI) Microsomal triglyceride transfer protein (MTP) inhibitors Acyl coenzyme A acyltransferase (ACAT) inhibitors Diacylglycerol acyltransferase (DGAT) inhibitors Thyroxin receptor agonists ApoB mrna antisense drugs PCSK9 antibodies ApoA1-based strategies (iv) Cholesterol ester transfer protein (CETP) inhibitors

44 Lipid Modifying Drugs Cholesterol absorption inhibitors Squalene synthase inhibitors (SSI) Microsomal triglyceride transfer protein (MTP) inhibitors Acyl coenzyme A acyltransferase (ACAT) inhibitors Diacylglycerol acyltransferase (DGAT) inhibitors Thyroxin receptor agonists ApoB mrna antisense drugs PCSK9 antibodies ApoA1-based strategies (iv) Cholesterol ester transfer protein (CETP) inhibitors

45 a yellow card...

46 Βοηθήστε να γίνουν τα φάρμακα πιο ασφαλή και Αναφέρετε ΟΛΕΣ τις ανεπιθύμητες ενέργειες για ΟΛΑ τα φάρμακα Συμπληρώνοντας την ΚΙΤΡΙΝΗ ΚΑΡΤΑ Αναφέρετε κάθε ύποπτη ανεπιθύμητη ενέργεια σύμφωνα με το εθνικό σύστημα αναφοράς στο Τμήμα Ανεπιθύμητων Ενεργειών του Εθνικού Οργανισμού Φαρμάκων (ΕΟΦ) Τηλ , Fax , με τη χρήση της Κίτρινης Κάρτας διαθέσιμη και στην ιστοσελίδα του ΕΟΦ, για έντυπη ή ηλεκτρονική υποβολή ή εναλλακτικά στην AMGEN Ελλάς Φαρμακευτικά Ε.Π.Ε. Τηλ.: AMG 145-GRC-AMG October-NP

47 Take Home Messages FH underdiagnosed and undertreated FH screening; do it! FH Kids: treat early... FH: novel Rx; just around the corner!

48 An interesting road ahead of us...