Presentation is loading. Please wait.

Presentation is loading. Please wait.

1464 Mo Renin inhibitors: the last challenge in the RAAS blockade Alberto Morganti U.O. Medicna Generale e Centro Ipertensione Arteriosa Ospedale San Giuseppe.

Similar presentations


Presentation on theme: "1464 Mo Renin inhibitors: the last challenge in the RAAS blockade Alberto Morganti U.O. Medicna Generale e Centro Ipertensione Arteriosa Ospedale San Giuseppe."— Presentation transcript:

1 1464 Mo Renin inhibitors: the last challenge in the RAAS blockade Alberto Morganti U.O. Medicna Generale e Centro Ipertensione Arteriosa Ospedale San Giuseppe Unversità degli Studi di Milano Tenth International Symposium Heart Failure Milan April,

2 1948 Mo Different Levels of Pharmacological Blockade of the Renin-Angiotensin System AngiotensinogenAsp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu-Val… Angiotensin I Asp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu Angiotensin II Asp-Arg-Val-Tyr-Lle-His-Pro-Phe Angiotensin(1,9) Angiotensin(1,7) Kidney: Na retention, fibrosis Heart: Hypertrophy (?), fibrosis Adrenals: Aldosterone release Vessels: Constriction, hypertrophy Brain: SNS activation, ADH release, thirst, salt appetite Liver Kidney, Adrenals, Retina, Ovaries, Testis Prorenin (Pro)renin receptors Renin Inactive peptides Bradykinin MasAT2AT1 ACE ACE2 ACE2 ACEACE ??

3 943 Mo Antagonism of the RAAS has been Proven Effective in: Essential hypertension Renovascular hypertension Pheochromocytoma Primary hyperaldosteronism? Acute and chronic heart failure Acute MI Cardiac arrhythmias Ischemic heart disease Stroke and TIA Dementia? Diabetic and nondiabetic nephropathy Proteinuria and non-proteinuric renal insufficiency Portal hypertension

4 Residual risk: morbidity and mortality remains high, despite treatment with ACEIs and ARBs Proportion died (%) Time (years) 12% relative risk reduction Residual Risk CHARM-Overall 1 : CV death 05001,0001, Population of patients Days of follow-up 22% relative risk reduction Residual Risk HOPE 2 : CV death, stroke and MI Proportion of patients with first event (%) Time (months) 14.6% relative risk reduction Residual Risk LIFE 3 : CV death, stroke and MI Event-free probability (%) Time post-randomization (months) 13.2% relative risk reduction Residual Risk Val-HeFT 4 : freedom from combined endpoint Placebo Ramipril Atenolol Losartan Valsartan Placebo 1 Pfeffer et al. Lancet 2003;362:759–66; 2 Yusuf et al. N Engl J Med 2000;342:145–53; 3 Dahlöf et al. Lancet 2002;359:995–1003; 4 Cohn et al. N Engl J Med 2001;345:1667–75 Placebo Candesartan

5 ACEIs and ARBs cause compensatory rises in PRA Glomerular vasoconstriction Inflammation Fibrosis Kidney Hypertrophy Fibrosis Vasoconstriction Heart Vasoconstriction Brain Hyperplasia hypertrophy Inflammation Oxidation Fibrosis Vessels Feedback Loop AT 1 Receptor Renin Ang I Angiotensinogen Ang II Biological effects ACE Non ACE pathways ARBs ACEIs PRA Adapted from: Müller DN & Luft FC. 2006

6 HYPERTENSION MI/CAD DEATHCHF DEATH or CV EVENTS Val-HeFT 4: 30% Vergaro 5 : 50% SAVE 3 : 100% Alderman 1 : 280% 1 Alderman et al. Am J Hypertens 1997;10:1–8 2 Bair et al. J Am Coll Cardiol 2009;53:A383 [Abstract] 3 Rouleau et al. J Am Coll Cardiol 1994;24:583–91 4 Latini et al. Eur Heart J 2004;25:292–9 5 Vergaro et al. Eur Heart J 2008;29(Suppl.):393 [Abstract] 6 Cohn et al. N Engl J Med 2001;435:1667–75 *Hospitalization for CHF; ACC: American College of Cardiology SAVE: Survival and Ventricular Enlargement study; Val-HeFT: Valsartan Heart Failure Trial Bair ACC : 40% Bair ACC : 106%* High PRA is associated with an increase in the incidence of events across the CVD continuum Time points: Alderman: 3.6 years (mean) SAVE: 38 months (mean) Bair ACC: >5 years Val-HeFT 6 : 23 months (mean) Vergaro: 23 months (mean) % = increased risk of event for high versus low PRA

7 1741 Mo Nonproteolytic Activation of Prorenin Bound to the (Pro)renin Receptor Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: Renin Prorenin AOG Ang I Ang II PRR PRR Nucleus Fibronectin Fibronectin Collagen I Collagen I ACEI ERK1/2 ERK1/2

8 Glaxo Wellcome Astra BMS Harvard Merck Dainippon Sankyo Kissei Zeneca Parke Davis Pfizer P&U Sanofi Fujisawa HMR Merck KGaA Roche Yamanouchi Abbott Searle SKB BI/Bio-Mega Wyeth-Ayerst Speedel Serie SPP800 Serie SPP1148 SPP635 Actelion/Merck Vitae/GSK Plexxikon/Servier 2007 Ricerca farmacologica e sviluppo dei DRIs Aliskiren

9 Wood JM, et al Aliskiren: the first orally available direct renin inhibitor Molecular weight = High solubility in water and biological fluids Non-peptide drug suitable for oral administration O N H CONH 2 OH H2NH2N CH 3 O O

10 Aliskiren si lega alla tasca secondaria S3sp della renina La tasca secondaria S3sp distingue la renina dalle altre aspartil proteasi. Il legame di aliskiren alla tasca secondaria S3sp della renina (alloggiandovi la catena secondaria metossialcossilica dellinibitore) è alla base della sua specificità per la renina umana rispetto alle altre aspartil proteasi. Adattato da: Wood JM et al, 2003

11 Direct renin inhibition acts at the point of activation of the Renin System and neutralizes the PRA rise Feedback Loop AT 1 Receptor Renin Ang I Angiotensinogen Ang II Direct renin inhibitor Biological effects ACE Non ACE pathways PRA Adapted from: Müller DN & Luft FC Glomerular vasoconstriction Inflammation Fibrosis Kidney Hypertrophy Fibrosis Vasoconstriction Heart Vasoconstriction Brain Hyperplasia hypertrophy Inflammation Oxidation Fibrosis Vessels

12 1683 Mo Inibitori Diretti della Renina Caratteristiche Farmacologiche di Aliskiren Potente e specifico inibitore non peptidico della renina umana (IC 50 = 0.6 nmol/L) Lunga emivita plasmatica (30-40 ore) Assorbimento rapido ma scarso e variabile; migliore a digiuno Binding alle proteine plasmatiche 50% Bassa biodisponibilità (2.6%) Lunga persistenza nei tessuti (specie nel rene) Escrezione prevalentemente per via fecale (90%)

13 1824 Mo Concentration of Aliskiren in the Circulation Fisher NDL et al., Circulation 2008; 117: Aliskiren conc. (ng/ml) Placebo 75 mg 150 mg 300 mg 600 mg Dose: Time(min): h h h h48h

14 2202 Mo Plasma Renin, Aliskiren/Renin Concentration Ratio, Percentage Renin Inhibition, PRA and Plasma AII Following Exposure to Escalating Doses of Aliskiren on Separate Study Days Danser JAH et al., Hypertension Research 2010; 34: 4-10 (ng/l) ReninRenin[Aliskiren]/[renin][Aliskiren]/[renin] Renin inhibition PRAPRA AIIAII (thousands) (%) (pg/ml) (ng AII l/ml.h)

15 2100 Mo Change in PRA in Patients Treated with Various Antihypertensives and Combination RAS Blockade Epstein BS et al., Expert Rev Cardiovasc Ther 2009; 7: PRA increase (%) CCBAmlodipineACEIRamiprilHCTZHCTZARBIrbesartanARB/HCTZValsartan/HCTZACEI/ARBBenazepril/valsartanDRIAliskirenDRI/ACEIAliskiren/ramipril

16 1839 Mo Renal Partitioning and Localization Pattern of Aliskiren Feldman DL et al., Hypertension 2008; 52: Aliskiren ( M) Aliskiren: 10 mg/kg 3 mg/kg 10 mg/kg Non-diabeticDiabetic Glomeruli Renal cortical artery

17 1934 Mo Krop M et al., Hypertension 2008; 52: Percentage of (pro)renin that is Aliskiren-bound in the Cell Lysates, Culture Medium, and Stimulation Medium of HMC-1 Cells after Incubation of Cells in the Absence or Presence of Aliskiren % aliskiren-bound Cell lysate Culture medium Stimulation medium log [aliskiren] (mol/l)

18 1742 Mo Potential Inhibition of Receptor-bound Activated Prorenin and of Renin and Receptor Interaction by Renin Inhibitor Blocking the Active Site of Renin and Modifying Its Conformation Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: ? Ang I Nucleus ERK1/2 ? Mature renin Renin inhibitor Prorenin

19 2213 Mo Changes in Systolic and Diastolic BP with Aliskiren according to Gender and Body Mass Index Jarugula V et al., J Clin Pharm, March 2010 Mean change in SBP Mean change in DBP (mmHg) Menn=468Womenn=298Menn=438Womenn=326 BMI < 30 n=512BMI 30 30n=250BMI < 30 n=491BMI 30 30n=269Aliskiren 150 mg Aliskiren 300 mg Aliskiren 150 mg Aliskiren 300 mg Menn=468Womenn=298Menn=438Womenn=326 BMI < 30 n=512BMI 30 30n=250BMI < 30 n=491BMI 30 30n=269Aliskiren 150 mg Aliskiren 300 mg Aliskiren 150 mg Aliskiren 300 mg

20 2206 Mo Change in Sitting Systolic and Diastolic BP with Aliskiren Monotherapy in Women, Analysed by Age Gradman AH et al., J Human Hypertens, March 2010 Mean change in msSBP Mean change in msDBP (mmHg) Aliskiren 150 mg Aliskiren 300 mg < 50 y y 100 > 55 y 244 n = < 50 y y 147 > 55 y 388 < 50 y y 100 > 55 y 244 n = < 50 y y 147 > 55 y 388 Aliskiren 150 mg Aliskiren 300 mg

21 2210 Mo Effect of Aliskiren Monotherapy and in Combination with Other Antihypertensive Agents in AGELESS Study Duprez A et al., J Human Hypertens, December 2009 Mean change in msSBP Mean change in msDBP (mmHg) Week 12 Week 22 Week 36 ± HCTZ ± Amlo RamiAli ± HCTZ RamiAliRami-prilAli-skiren Week 12 Week 22 Week 36 ± HCTZ ± Amlo RamiAli ± HCTZ RamiAliRami-prilAli-skiren P = 0.03 P = 0.14 P < 0.01 P = 0.07 P = 0.03 P = 0.02

22 2103 Mo Systolic and Diastolic Blood Pressure during the Post-active-controlled-treatment with Aliskiren and Ramipril Andersen K et al., J Renin Angiotensin Aldosterone Syst 2009; 10: SBPSBPDBPDBP mmHgmmHg WeekWeek

23 Aliskiren provides significant reductions in PRA compared with placebo Mean change from baseline in PRA at Week 12 (ng/mL/h) Optimal HF therapy + Aliskiren150 mg Optimal HF therapy + Placebo *p< vs placebo McMurray JJV. ESC 2007 (ALOFT) n= n= *

24 Aliskiren provides significant reductions in urinary aldosterone levels compared with placebo Mean change from baseline in urinary aldosterone at Week 12 (nmol/day) –4 –2 0 Optimal HF therapy + Aliskiren150 mg –6 –8 n=128n=141 –9.2 –7.0 –10 *p=0.015 vs placebo * Optimal HF therapy + Placebo McMurray JJV. ESC 2007 (ALOFT)

25 Aliskiren provides significant reductions in BNP levels compared with placebo Mean change from baseline in BNP at Week 12 (pg/mL) Optimal HF therapy + Aliskiren 150 mg Optimal HF therapy + Placebo 60 n=137n= p= Baseline BNP concentration = 291 pg/mL McMurray JJV. ESC 2007 (ALOFT)

26 1832 Mo Changes in Albumin Excretion Rate in Patients with Diabetes and Hypertension Treated with Losartan Alone or in Combination with Aliskiren Parving HH et al., NEJM 2008; 358: Urinary albumin-to-creatinine ratio Urinary Urinary albumin excretion rate Urinary albumin excretion rate Mean sitting blood pressure Mean sitting blood pressure S D % % mmHg WeekWeekWeek

27 1684 Mo Conclusioni Aliskiren è il primo di una nuova classe di farmaci che antagonizzano lattività del SRAA inibendo direttamente lattività enzimatica della renina Aliskiren è lunico farmaco che inibisce i meccanismi di controregolazione che possono limitare lefficacia degli altri bloccanti del SRAA (ACEI/ARB) In studi controllati la riduzione della pressione arteriosa indotta da aliskiren è uguale o superiore a quella di alcuni ACEI/ARB Grazie alla elevata concentrazione a livello renale e alla interferenza del binding di renina e prorenina agli specifici recettori, aliskiren potrebbe esercitare effetti locali di protezione dorgano indipendenti dalleffetto antipertensivo


Download ppt "1464 Mo Renin inhibitors: the last challenge in the RAAS blockade Alberto Morganti U.O. Medicna Generale e Centro Ipertensione Arteriosa Ospedale San Giuseppe."

Similar presentations


Ads by Google