Prise en charge des dyslipidemies en 2016: on fait quoi du LDL?

Transcription

1 Prise en charge des dyslipidemies en 2016: on fait quoi du LDL? Professeur Atul PATHAK Clinique Pasteur Université de Toulouse INSERM 1048

2 Declaration de Relations Professionnelles Prise en charge de ma participation par les laboratoires El Kendi.

3 Clint Eastwood est le bon..qui est la brute? Qui est le truand?

4 Quel sont les questions en suspens? Le LDL : est ce la bonne cible? Le traitement par statine toujours d actualité? Laquelle, Chez qui, Quelle dose Statine seule ou en association? Les effets indésirables? Les nouveaux traitements.

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6 Sur le plan pharmacodynamique L effet sur le LDL prime La notion des effets pleïotropes n a pas démontré un bénéfice clinique Message général pour tous les médicaments passés ou à venir

7 Pathologies Critères Intermédiaires Critères Cliniques HTA PSA AVC, IDM, Mortalité Hypercholestérolémie Cholestérolémie IDM, Mortalité Diabète Glycémie, Hb glyquée Microangiopathie Mortalité Ostéoporose Densité osseuse Fractures (col, vertèbres) Cancer Taille de la tumeur Survie (comment?) Hépatite C Bio marqueurs périphériques Fibrose hépatique Mortalité Infarctus du myocarde Hyperexcitabilité ventriculaire Mort subite Ménopause Troubles métaboliques Accidents cardiovasculaires

8 Synthèse prévention primaire

9 Synthèse prévention secondaire CTT collaborators Lancet 2012; 380: 581

10 Au Maghreb, peu d études, niveau de risque (diabétique, Fast Food..)

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13 6 La seule alternative aux statines : Les RHD

14 6 La seule alternative aux statines : Au dela des RHD augmenter les doses pour baisser davantage le LDL

15 First Major CV Event (%) TREATING TO NEW TARGETS (TNT) Intensive LDL-C reduction and Residual Risk of Major Cardiovascular Events* % 8.7% Relative Risk 22% Modifiable Risk Factors Etc. RESIDUAL CV RISK CT-HDL, TG Blood pressure IA fat (obesity) Inulin-resistance Smoking Inflammation 2 0 HR 0.78 ( ) P< Duration of Treatment (years) Non Modifiable Risk Factors Age Gender Family history Atorvastatin 10 mg/d (n=5006) Atorvastatin 80 mg/d (n=4995) * CHD death, non-fatal MI, fatal and non-fatal stroke La Rosa 2005

16 Les développements à venir donnent raison au tout LDL

17 Evolocumab (AMG 145): Programme PROFICIO Statinintolerant Monotherapy Combotherapy HeFH HoFH/ Severe HeFH Open-label Extension Secondary Prevention IVUS Plaque Atherome Phase 2 (N = 631) Phase 2 (N = 411) Phase 2 (N = 157) Phase 2 (N = 161) Phase 2/3 (N < 67) Phase 2 (N > 1000) Phase 3 (N = 1700) Phase 3 (N = 600) Phase 3 (N = 300) Phase 3 (N = 300) Phase 3 (N = 75) Phase 3 (N < 3800) Phase 3 (N = 22500) Phase 3 (N = 900)

18 Alirocumab : ODYSSEY Phase 3 Clinical Trial 14 global phase 3 trials including >23,500 patients across >2,000 study centers HeFH population HC in high CV risk population Additional populations Add-on to max-tolerated statin (± other LMT) ODYSSEY FH I (NCT ; EFC12492) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=471; 18 months ODYSSEY FH II (NCT ; CL1112) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=250; 18 months Add-on to max-tolerated statin (± other LMT) ODYSSEY COMBO I (NCT ; EFC11568) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=306; 12 months *ODYSSEY COMBO II (NCT ; EFC11569) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=660; 24 months ODYSSEY MONO (NCT ; EFC11716) Patients on no background LMTs LDL-C 100 mg/dl N=100; 6 months ODYSSEY ALTERNATIVE (NCT ; CL1119) Patients with defined statin intolerance LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=250; 6 months ODYSSEY HIGH FH (NCT ; EFC12732) LDL-C 160 mg/dl N=105; 18 months ODYSSEY CHOICE I (NCT ; CL1308) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=700; 12 months ODYSSEY OLE (NCT ; LTS 13463) Open-label study for FH from EFC 12492, CL 1112, EFC or LTS N 1000; 30 months ODYSSEY LONG TERM (NCT ; LTS11717) LDL-C 70 mg/dl N=2,100; 18 months ODYSSEY OUTCOMES (NCT ; EFC11570) LDL-C 70 mg/dl N=18,000; 64 months ODYSSEY CHOICE II (NCT ; EFC13786) Patients not treated with a statin LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=200; 6 months ODYSSEY OPTIONS I (NCT ; CL1110) Patients not at goal on moderate dose atorvastatin LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=350; 6 months ODYSSEY OPTIONS II (NCT ; CL1118) Patients not at goal on moderate dose rosuvastatin LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=300; 6 months FH=familial hypercholesterolemia; HC=hypercholesterolemia; LMT=lipid-modifying therapy; OLE=open-label extension. *For the ODYSSEY COMBO II other LMT not allowed at entry. ClinicalTrials.gov. ODYSSEY Phase 3 Trials. Accessed February 12, 2014.

19 Calculated LDL-C, LS mean (SE), mg/dl Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks Achieved LDL-C Over Time All patients on background of maximally tolerated statin ± other lipid-lowering therapy Alirocumab Placebo mg/dl (+0.8%) mg/dl (+4.4%) Difference 61.9% Difference 61.3% 48.3 mg/dl ( 61.0%) 53.1 mg/dl ( 56.8%) Week 19 Intent-to-treat (ITT) analysis

20 Estimated probability of event Post-hoc Adjudicated Cardiovascular TEAEs (Same as primary endpoint of ongoing ODYSSEY OUTCOMES trial ) Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) 0.10 Placebo + max-tolerated statin ± other LLT Alirocumab + max-tolerated statin ± other LLT In one of the largest evaluations of Cox model analysis: HR=0.46 (95% CI: 0.26 to 0.82) Nominal p-value = <0.01 Mean treatment duration: 65 weeks patients with pharmacologicallyinduced LDL-C < 25 mg/dl, no safety signals were observed. No. at Risk Placebo Alirocumab Weeks 20 Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy

21 Les strategies en plus des statines Further LDL-C reduction (Apo B) High potency Statins Statins and Ezetimibe STATINS On Optimal LDL-C levels APO B NON-HDL Cholesterol HDL LDL IDL VLDL Impact on HDL-C and TG Statin+CETP inhibitors Statin+Fenofibrate Statin+Nicotinic Acid Statin+Fish oil (only effective on TG)

22 Change in HDL-C from Baseline (%) ILLUMINATE Trial: Effects of Torcetrapib in Patients at High Risk for Coronary Events p=< % 2.0% Death from Any Cause p= Atova+Torcetrapib Atorva Atova+Torcetrapib Atorva N = 7534 N = 7533 N = 7534 N = 7533 ILLUMINATE trial was terminated prematurely (median f-up 550 days) because of an increased risk of death and cardiac events in patients receiving torcetrapib Barter PJ et al. N Engl J Med 2007;357:

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24 CETP Inhibitors F F F F F F F F F N o o o Molecular weight F Dalcetrapib Torcetrapib Anacetrapib CETP binding site Cys 13 residue 1 Helices at the end of the C and N barrels 2? (Similar to torcetrapib) 3 CETP inhibition 37.2% 5 80% 6 90% 3 LDL-C levels No effect 25% decrease 35-40% decrease HDL-C levels Blood pressure 26.5% 5 increase (600 mg dose) May 7 th, 2012 Roche stopped daloutcomes phase III trial due to 91% 6 increase 129% 7 increase terminated prematurely because of increased increase No 8 Yes 9 No lack of clinical 3 meaningful results. Dal-HEART stopped as well! risk of death and cardiac events in patients receiving torcetrapib Increases aldosterone No 8 Yes 8 No 10 1 Okamoto et al. Nature. 2000;406: ; 2 Clark et al. J Lipid Res. 2006;47: ; 3 Masson D. Curr Opin Invest Drugs. 2009;10: ; 4 Ranalletta et al. J Lipid Res. 2010; in press; 5 de Grooth et al. Circulation. 2002;105: ; 6 Clark et al. Arterioscler Thromb Vasc Biol. 2004;24: ; 7 Krishna et al. Lancet. 2007;370: ; 8 Stein et al. Am J Cardiol. 2009;104:82 91; 9 Barter et al. N Engl J Med. 2007;357: ; 10 Forrest et al. Br J Pharmacol 2008;154:

25 Les medicaments en plus des statines Further LDL-C reduction (Apo B) High potency Statins Statins and Ezetimibe STATINS On Optimal LDL-C levels APO B NON-HDL Cholesterol HDL LDL IDL VLDL Impact on HDL-C and TG Statin+Fenofibrate Statin+Nicotinic Acid Statin+Fish oil (only effective on TG)

26 Proportion with Event (%) 2 Caso Clinico A. Zambon ACCORD: Primary endpoint Major CV events (overall population) Placebo (95% CI ), p= Fenofibrate No. At Risk Fenofibrate Placebo Years Major CV events defined as CV death, nonfatal MI and nonfatal stroke This article ( /NEJMoa ) was published on March 14, 2010, at NEJM.org

27 Les strategies en plus des statines Further LDL-C reduction (Apo B) High potency Statins Statins and Ezetimibe STATINS On Optimal LDL-C levels APO B NON-HDL Cholesterol HDL LDL IDL VLDL Impact on HDL-C and TG Statin+CETP inhibitors Statin+Fenofibrate Statin+Nicotinic Acid Statin+Fish oil (only effective on TG)

28 LDL Cholesterol (mg/dl) HDL Cholesterol (mg/dl) AIM-HIGH: Lipid Parameters and Primary End Point mg/dl 42 mg/dl 38 mg/dl Monotherapy Combination Therapy Baseline 1 Year 2 Years 3 Years Time of Visit mg/dl Monotherapy Combination Therapy 67 mg/dl 62 mg/dl Baseline 1 Year 2 Years 3 Years Time of Visit The on-treatment difference in HDL-C between groups was only 4 mg/dl The on-treatment difference in LDL-C between groups was only 5 mg/dl Published on November 15, 2011, at NEJM.org.

29 Donc alternative pas possible, combinaison pas efficace on en revient à une baisse du LDL par statine (anti PCSK 9 pas d études de morbi mortalité)

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31 pravastatine pravastatine

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33 Calcul SCORE = Risque de mortalité cardiovasculaire à 10 ans Homme 55 ans Fumeur TA : 145 / 85 mm Hg CT : 2,35 g/l HDL-C : 0,33 g/l TG : 2,25 g/l LDL-C : 1,57 g/l Glyc : 1,07 g/l IMC : 30,5 kg/m² Tour Taille : 112 cm Total cholesterol (mmol/l, mg/dl)

34 Quel est l objectif LDL-C? LDL-C < 0,70 g/l Ou > 50% réduction de LDL LDL-C < 1,00 g/l LDL-C < 1,15 g/l Pas de Statine (sauf si LDL-C très élevé) MCV documentée SCORE 10% IRC sévère (< 30) DT + 1 FR et/ou org. DT 0 FR SCORE 10-5% IRC modérée (30-59) FR extrêmes SCORE 5-1% SCORE < 1% Très Haut Risque Haut Risque Risque Modéré Bas Risque ESC/EAS Guidelines. Eur Heart J 2011; 32:

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36 Efficacité sur la mortalité toutes causes

37 Efficiences des Statines: quel prix êtes vous prêt à mettre pour baisser le LDL? Couteux Economique Faible reduction Forte reduction

38 Prise en charge des dyslipidémies athérogènes : un puzzle simplifié. LDL élevés Statines Morbidité Mortalité Recommandations Medicoéconomique

39 Au total, augmentation des doses de statine pour contrôler le LDL- Cholstérol et seulement statines Cible reconnue Uniquement le LDL Efficacité pharmacodynamique Réduction par statine, à la bonne dose Bénéfice dans les essais cliniques Pour les statines en prévention I et II Risque maîtrisés Effets indésirables, connus et attendus Solution efficiente Balance Benefice/ risque / economie en faveur.