«Πόσο αποτελεσματική και ασφαλής είναι η μείωση της LDL με τα νεότερα φάρμακα»

«Πόσο αποτελεσματική και ασφαλής είναι η μείωση της LDL με τα νεότερα φάρμακα» Γενοβέφα Κολοβού, MD, PhD, FESC, SFASA, FRSH Υπεύθυνη Εξωτερικών Ιατρείων και Προληπτικής Καρδιολογίας Υπεύθυνη Λιπιδαιμικού Ιατρείου και LDL Αφαίρεσης

Δήλωση σύγκρουσης συμφερόντων Τα τελευταία 2 χρόνια Συμμετοχή στις μελέτες με: MIPO, PSCK9 Attended conferences, advisory boards and gave talks sponsored by MSD, Astra Zeneca, Abbott, Amgen, Sanofi, Lilly, ELPEN Chairperson: Expert Panel on 1. Postprandial Lipemia, 2. Longevity Syndrome

«Πόσο αποτελεσματική και ασφαλής είναι η μείωση της LDL με τα νεότερα φάρμακα» Resveratrol Pitavastatin CETP inhibitors Mipomersen PCSK9 MTP inhibitors

Resveratrol Stilvid* Ρεσβερατρόλη Polyphenolic compound found in fresh grapes, grape juice, and wine. Resveratrol is produced by the skin of grapes in response to fungal exposure. Trans-resveratrol up-regulated hepatic LDLR expression via proteolytic activation of sterol regulatory element binding protein 1c (SREBPs). *Stilvid 8mg resveratrol

Resveratrol Ρεσβερατρόλη Protects the CV system by: 1. Inhibition of LDL oxidation, 2. Inhibition of PLTs aggregation, 3. Synthesis of pro-atherogenic eicosanoids, 4. Inhibition of cell proliferation, 5. Increased vasorelaxation. 6. Suppresses TF

RESVERATROL! Meta-of conclusive result on the lipid-modulating effects of resveratrol! 7 randomized controlled trials, 282 subjects (141 in each group) met the eligibility criteria!!tc: -8.70!!LDL -3.22! HDL -0.26! TGs -4.30! Not dependent on the resveratrol dose Sahebkar A1.Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2013 Dec;71:822-35.

RESVERATROL! Αϋπνία! Αρθρίτιδα και πόνος στις αρθρώσεις! Αύξηση της AΠ! Αίσθηµα παλµών

Figure 1 Role of LXR in cholesterol metabolism. Ανάστροφη µεταφορά της χοληστερόλης Zhao C, Dahlman-Wright K J Endocrinol 2010;204:233-240

Figure 1 Role of LXR in cholesterol metabolism. RESVERATROL Ανάστροφη µεταφορά της χοληστερόλης Zhao C, Dahlman-Wright K J Endocrinol 2010;204:233-240

EXPERT OPINION: As LXR agonists have the potential to be useful for many indications, the scientific community, despite setbacks due to on-target side effects, has maintained interest and devised strategies to overcome safety hurdles. While a clinical proof of concept still remains elusive, the recent advancement of compounds into the clinic highlights that acceptable safety margins in preclinical species have been achieved. Loren J, et al. Liver X receptor modulators: a review of recently patented compounds (2009-2012). Expert Opin Ther Pat. 2013;23:1317

IMPROVING LDL-TARGET ATTAINMENT RATES IN CLINICAL PRACTICE Statins vary in their ability to! HDL-C

High HMG-CoA reductase inhibition and affinity in vitro (Wistar Rats) Pitavastatin inhibited HMG-CoA reductase in a concentration-dependent manner more potently than Simvastatin or Pravastatin

Pitavastatin increases HDL-C levels Mechanism of action " " HepG2

Effect of statins on ApoAI production Pitavastatin Atorvastatin Simvastatin Hep G2 cells were treated for 48h with various concentrations of statins (1 30 µm and 50 µm). The apoai in the cultured medium was determined by ELISA kit. *p<.05, p<.001, p<.01, Dunnett s test.

Pitavastatin vs Atorvastatin Change from baseline in LDL-C (mg/dl)

Pitavastatin: beyond LDL lipid-lowering (I)!TGs "TG-rich VLDL from rat liver "Migration and proliferation of rat SMCs Prevents! in intima media thickness (Rabbits) " Oxidised-induced foam cell formation Stabilises plaque (Watanabe heritable hyperlipidaemic rabbits)

Pitavastatin: preclinical effects beyond lipid-lowering (II) Competitive HMG-CoA reductase inhibition ( cholesterol synthesis, ApoB degradation, VLDL, IDL) ox-ldl-induced foam cell formation fibronectin accumulation SMC proliferation and IMT (18%, 57%, 70% at 0.1, 0.3, 1.0 mg/kg in balloon-injured carotid artery)

Pitavastatin significantly reduced serum hs-crp independently of improved lipid profiles Effect of Pitavstatin 1-2 mg/day on hs-crp levels (mg/l) Subjects with Type 2 Diabetes (hs-crp) - 39% after 12 months

2013, ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

Dietary C A B C G RCT C C C A B C A1 C C CETP sd LDL TG LDL TG rich Lps EC TG EC VLDL SRB1 HDL Pro HDL LCAT CETP sd HDL Kolovou, et al Cholesterol ester transfer protein (CETP), postprandial lipemia and hypolipidemic drugs. CMC, 2009

! At present anacetrapib by Merck and evacetrapib by Eli Lilly are under development.! Anacetrapib 100mg " HDL-C by 138%,! LDL 40%.! Evacetrapib 500 mg "HDL-C by 132%!LDL by 40%

Rationale of developing CETP inhibitors! Naturally CETP-deficient mice No atherosclerosis, but CETP-transgenic mice Yes atherosclerosis! HoCETP-deficient patients No atherosclerotic CVD! " HDL-C subjects due to CETP-deficiency No

Rationale of developing CETP inhibitors! CETP-inhibitor: " HDL-C and! LDL-C as observed in HoCETP-deficiency! In human CETP-deficiency: plasma!cetp mass and!cetp activity! In subjects treated by CETP inhibitors: "CETP complex but! CETP activity

Rationale of developing CETP inhibitors! Anti-synthetic drug of CETP like antisense oligonucleotide inhibitor of human CETP will:!cetp mass and CETP activity, and! atherosclerosis " fecal cholesterol excretion

CETP like antisense oligonucleotide inhibitor! The small molecule inhibitor (SMI) such as anacetrapib, bind and inactivate CETP associated with the HDL particle,! CETP ASO degrades CETP mrna, thus significantly lowering the amount of protein that is synthesized in the liver Mabuchi H, et al. Cholesteryl Ester Transfer Protein (CETP) Deficiency and CETP Inhibitors. Mol Cells. 2014 Nov 30;37(11):777-784.

CETP like antisense oligonucleotide inhibitor! Treatment by ASO produce similar phenotypic features to human CETP deficiency! In CETP tg LDLr-/- mice, antisense oligonucleotide decreased CETP protein, but by anacetrapib CETP protein was greatly increased and made a complex with HDL fraction Mabuchi H, et al. Cholesteryl Ester Transfer Protein (CETP) Deficiency and CETP Inhibitors. Mol Cells. 2014 Nov 30;37(11): 777-784.

CETP inhibitors! Η ανακετραπίµπη και η νταλκετραπίµπη, υποβάλλονται στη φάση ΙΙΙ των κλινικών δοκιµών [dal-outcomes και HPS3/ REVEAL (Randomized evaluation of the effects of anacetrapib through lipid modification)] και τα αποτελέσµατα αναµένονται το 2013 και 2017, αντιστοίχως, ενώ η µελέτη για την εβακετραπίµπη είναι ακόµη στη φάση ΙΙ των κλινικών δοκιµών Shinkai H. Vasc Health Risk Manag. 2012

REVEAL HPS-3 TIMI-55 trial Will include 30 000 with occlusive arterial disease pts treated with ATV therapy and anacetrapib or placebo To be completed 2015-2016

Πέραν των στατινών: νέοι θεραπευτικοί παράγοντες Norata G.D. et al Eur Heart J 2013; 380:29-36

Mipomersen: Mechanism of Action DNA mrna Disease-Associated Protein Traditional Drug Transcription Translation Transcription No Translation Antisense Drug (Oligonucleotide) No Disease-Associated Proteins Produced Crooke R, et al. Adapted from: Crooke ST, ed. Antisense drug technology: principles, strategies and applications. 2nd ed. Boca Raton, FL: CRC Press, 2007:601-639.

Apo B inhibitor Double-blind, placebo-controlled, mipomersen, in pts with statin intolerant, for 28 weeks 33 pts sc 200 mg/weekly mipomersen or placebo LDL: 47%, apob 46%: Lp(a) 27% 19% mipomersen and 17% placebo discontinued Liver transaminase increases 3 in mipomersen 33% Visser, et al. Eur Heart J. 2012 May;33(9):1142-9

PCSK9 Προ-πρωτεΐνη PCSK9 Proprotein Convertase Subtilin/Kexin 9 gene

PCSK9 FH

PCSK9 Inhibitors Ο PCSK9 αναστολέας είναι ένα ανθρώπινο αντίσωμα, το οποίο αδρανοποιεί την πρωτεΐνη PCSK9, μέσω δέσμευσής της στη δομική περιοχή του LDLR, προστατεύοντας, έτσι, την καταστροφή του LDLR

Ανακύκλωση Ηπατοκύτταρο Καταστροφή των LDLR LDLR Σύνθεση/ορίµανση Των LDLR Λυσόσωµα LDL Golgi PCSK9 Aυτοκαταλυτική διεργασία Κυκλοφορία Κολοβού Γ, Οικογενής υπερχοληστερολαιμία, Σιτοστερολαιμία, 2012, INFOHEALTH

PCSK9 OSLER Study 1359 pts, phase 2 study Sc evolocumab 420 mg/4 weeks 52 weeks of follow-up! 52% in LDL-C at week 52 Koren MJ et al. OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014 Jan 14;129(2):234-43.

PCSK9 7 studies # phase II/III trials evaluated REGN727/ SAR236553 or AMG145 in pts with hfh!ldl-c when added to conventional lipid-lowering therapy Ling et al. An update on the clinical development of proprotein convertase subtilisin kexin 9 inhibitors, novel therapeutic agents for lowering low-density lipoprotein cholesterol. Cardiovasc Ther. 2014 Apr;32(2):82-8.

PCSK9 MENDEL-2 Study 614 pts! LDL-C by 55-57% vs placebo! LDL-C by 38-40% vs ezetimibe Koren et al. MENDEL-2 Investigators. Anti-PCSK9 Monotherapy for Hypercholesterolemia - The MENDEL-2 Randomized, Controlled Phase 3 Clinical Trial of Evolocumab. J Am Coll Cardiol. 2014 Mar 25.

PCSK9 Statins Statin "PCSK9 Atorvastatin " PCSK9 by 34% with 40 mg/d " PCSK9 by 47% with 80 mg/d

PCSK9 Statins Rosuvastatin 20 mg (JUPITER) " PCSK9 by 28% in men and 35% in women

MTP inhibitor, Lomitapide " LDL 46% Kolovou G, et al. Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings and Clinical Significance. Cardiovasc Therap, 2015

Until today, patient is taken lomitapde 20 mg/daily nearly 8 months. LDL apheresis is performed every 2.5-3 months. His total cholesterol is usually <300 mg/dl and LDL-C <250 mg/dl. Beside few gastrointestinal complains no other side effects were notice.

Εντερικός αυλός Εντεροκύτταρο Λέµφος Διατροφή Χολή Μικκύλια NPC1L1 ACAT2 MTP Χυλοµικρά Apo B48 ABCG5 ABCG8 Χοληστερόλη Κόπρανα Φυτοστερόλη Κολοβού Γενοβέφα, Οικογενής υπερχοληστερολαιμία, Σιτοστερολαιμία, 2012 εκ. INFOHEALTH

Κλόουν Γενοβέφα Kολοβού Λάδι 2000