UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION

NEWER MOLECULES AND TRIALS

RAAS INHIBITION

POINTS FOR DISCUSSION

• NEWER UNDERSTANDING IN THE RAAS• RECENT LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION

ANGIOTENSIN II – CENTRAL ROLE

High CV RiskPost MI

Hypertension

Myocardialinfarction &

stroke

RemodellingVentricular dilation/

cognitive dysfunction

Congestive heart failure/secondary stroke

Micro-albuminuria

Heart Failure

Atherosclerosisand LVH

Macro-proteinuria

Nephroticproteinuria

Endothelialdysfunction

End-stageheart disease,brain damageand dementia

Cardio/cerebrovascular

death

Hypertension risk factorsdiabetes, obesity, elderly

End-stagerenal

disease

Adapted from Dzau V. and Braunwald E., Am Heart J 1991;121:1244–1263

CURRENT VIEW

NEW CONCEPTS • PRO-RENIN • LOCAL RENINS• EXTRA RENAL RAS• INTRA CELLULAR RAS• ACE 2 • AT 2 RECEPTORS• CHYMASE PATHWAYS• MAS RECEPTOR AXIS

POINTS FOR DISCUSSION

• NEWER UNDERSTANDING IN THE RAAS

• SOME LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION

HBPHBP VASCULARVASCULAR MIMI HFHF

PRE-DIABETESPRE-DIABETES DIABETES DIABETES OPTHALOPTHAL

DIABETES RENALDIABETES RENAL

(DIRECT)(DIRECT)

LIFE LIFE

SCOPESCOPEOPTIMAALOPTIMAAL

CHARMCHARM VALUEVALUE

VALIANTVALIANT

(NAVIGATOR)(NAVIGATOR)

(ONTARGET)(ONTARGET)(TRANSCEND)(TRANSCEND)

JIKEIJIKEI

ELITE IIELITE II

Val-HeftVal-Heft

RENAALRENAAL

IDNTIDNT

AT1-Receptor Blocker (ARB)

ATRIAL FIBATRIAL FIB (ACTIVE)(ACTIVE)

(I-PRESERVE)(I-PRESERVE)

Clinical Outcome StudiesClinical Outcome Studies

Current Trial Programmes Cover the LargestPopulation of CV High Risk Patients

High CV RiskHOPE, EUROPA,PEACE, QUIET

ONTARGETTRANSCEND

PROfESS

RemodellingVentricular dilation/

cognitive dysfunction

Post MISAVE AIRE; TRACE

OPTIMAL,VALIANT

Heart FailureCHARM, ValHeFT

EPHESUSHypertension

LIFE etc

73 million*Atherosclerosis

and LVH

Myocardialinfarction &

stroke

Micro-albuminuria

Endothelialdysfunction

Macro-proteinuria

Congestive heart failure/secondary stroke

End-stageheart disease,brain damageand dementia

Cardio/cerebrovascular

death

Nephroticproteinuria

Hypertension risk factorsdiabetes, obesity, elderly

End-stagerenal

disease

Summary: Reduction of NeuroendocrineActivation by Target Doses

Major Studies in RAS-Inhibition

0.25(HOPE Composite)Global Protection

HOPE Placebo0.20 ONTARGET

RamiprilTelmisartan

Telmisartan/Ramipril0.15Ramipril

Placebo

0.10Telmisartan

TRANSCEND

0.05

0.00

0 360 720 1080 1440 1800 2160

AS-as7-0908Days of follow-up

Major Studies in RAS-Inhibition

0.25(HOPE Composite)

HOPE ONTARGET

RamiprilTelmisartan

Telmisartan/Ramipril

0.20Placebo

0.15Ramipril

Placebo

0.10Telmisartan

TRANSCEND

0.05

Unmet medical need0.00

0 360 720 1080 1440 1800 2160

AS-as7-0908Days of follow-up

RECENT Studies of Olmesartan in Diabetes

ROADMAP(RANDOMISED OLMESARTAN AND DIABETES MICROALBUMINURIA PREVENTION STUDY)

Benefit of ARB + ACE inhibitor in HF

0.6 1.20.8

ARB+ACEI better

1.0

CHARM(HF)

1.4

ACEI alone better

VALIANT(post MI + HF/LV dysfunction)

Val-HeFT(HF)

1.20.8

HF hospitalization

1.0 1.40.6

All-cause mortality

ARB+ACEI better

ACEI alone better

Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.

ARBs in LV dysfunction: Before/after CHARM and VALIANT

Before CHARM, VALIANT

After CHARM, VALIANT

ARBs superior to ACEI? No (ELITE II, OPTIMAAL) No

ARBs non-inferior to ACEI? ? (ELITE II, OPTIMAAL) Yes

ARBs additive on top of ACEI? ? (Val-HeFT)

Yes, HFNo, post-MI

Combination ARB, ACEI, and β-blocker dangerous? ? (ELITE II, Val-HeFT) No

Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.

POINTS FOR DISCUSSION

• NEWER UNDERSTANDING IN THE RAAS• SOME LAND MARK TRIALS

• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION

NEW THERAPEUTIC APPROACHES

1. RENIN INHIBITION

2. ACE INHIBITION

3. AT1R BLOCKADE

4. AT2R STIMULATION

5. (P)RR BLOCKADE– ANGIOTENSIN-INDEPENDENT

SIGNALING

6. NEP INHIBITION– COMBINED VASOPEPTIDASE (NEP

PLUS ACE) INHIBITION

7. ALDOSTERONE-RECEPTOR BLOCKADE OR ALDOSTERONE-SYNTHASE INHIBITION

8. NO–CGMP STIMULATION

Nat. Rev. Cardiol. 7, 431–441 (2010)

NEWER RAS INHIBITORS ON THE WALL

Nat. Rev. Cardiol. 7, 431–441 (2010);

DIRECT RENIN INHIBITORS

1980 -INTRODUCED PEPSTATIN - THE FIRST SYNTHETIC RENIN INHIBITOR

BUT REQUIRED PARENTERAL ADMINISTRATION.

ORAL AGENTS : ENALKIREN, REMIKIREN, AND ZANKIREN HAD LIMITED CLINICAL USE

POOR BIOAVAILABILITY (<2%) SHORT HALFLIVES WEAK ANTIHYPERTENSIVE ACTIVITY .

ALISKIRENALISKIREN

OCTANAMIDE, NEW CLASS NONPEPTIDE, LOW MOLECULAR WEIGHT, ORALLY EFFECTIVE

AT A DOSE OF 300 MG DECREASES PRA BY 50–80%

THE PLASMA HALF-LIFE OF 23–70 HOURS

ALISKIREN

METABOLISM BY CYTOCHROME P450 (CYP3A4)

NO CHANGE OF DOSE IN HEPATIC AND RENAL INSUFFICIENCY

ADVERSE EVENTS : DIARRHEA, HEADACHE, NASOPHARYNGITIS, DIZZINESS, FATIGUE, BACK PAIN, GASTROINTESTINAL DISORDERS, RASH, AND RENAL STONE ,COUGH AND ANGIOEDEMA

ALSKIREN -TRAILS

ALSKIREN -TRAILS

ATMOSPHERE- ACUTE & CHRONIC CCF

VASOPEPTIDASE INHIBITORS

• KNOWN DRUGS OMAPATRILAT, SAMPATRILAT– TRIALS: OVERTURE AND OCTAVE– EFFECTIVE IN THE TREATMENT

OF HYPERTENSION AND HEART FAILURE

– ?ANGIOEDEMA

Nat. Rev. Cardiol. 7, 431–441 (2010);

ALDOSTERONE ANTAGONISM

ALDOSTERONE-SYNTHASE INHIBITORS

• NONINFERIOR TO AND BETTER TOLERATED• EFFICACY IN CONDITIONS WITH LOW ALDOSTERONE LEVELS ?

• FAD286 (NOVARTIS; BASEL, SWITZERLAND), – AN ENANTIOMERE OF FADRAZOL(CYP11B2)– LOWERED BLOOD PRESSURE IN RATS OVER EXPRESSING RENIN AND

ANGIOTENSINOGEN– AMELIORATED CARDIAC AND RENAL TARGET-ORGAN DAMAGE

• SPP2745 (SPEEDEL PHARMACEUTICALS; BASEL, SWITZERLAND) – GOOD SPECIFICITY, – PROTECTION TO THE CARDIAC, RENAL, AND VASCULAR SYSTEMS– COMPATIBLE WITH CONVENTIONAL RX

CALCIUM CHANNEL BLOCKERS AS RAS INHIBITORS

CALCIUM CHANNEL BLOCKERS

RECENT EVOLUTION OF DUAL AND TRIPLE COMBINATIONS.

In 2009, the US Food and Drug Administration approved the fixed combination of aliskiren/valsartan at the dosages of 150/160 mg and 300/320 mg for the treatment of hypertension in patients not adequately controlled on aliskiren or ARB monotherapy and as initial therapy in patients likely to need multiple drugs to achieve their BP goals

POINTS FOR DISCUSSION

• NEWER UNDERSTANDING IN THE RAAS• RECENT LAND MARK TRIALS• NEWER MOLECULES

• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION

American Society of Nephrology Oct, 30th 2009

SECONDARY END POINT QUALITATIVE DATA OF BLINDED ONE-YEAR BLOOD PRESSURE REDUCTION

Key Message:

OLMESARTAN CONFERRED VASCULAR PROTECTION BY DELAYING THE OCCURRENCE OF MICROALBUMINURIA (RISK REDUCTION OF 23%) AND CONTROLLING BLOOD PRESSURE IN PATIENTS WITH TYPE 2 DIABETES

OLIVUSTRIAL

Impact of OLmesarten on progression ofcoronary atherosclerosis: evaluation by IntraVascular UltraSoundOlivus study provides confirmation that

Olmesartan can retard progression of coronary atherosclerosis, the underlying cause of heart disease

J Am Coll Cardiol 2010;55:976–82

OLIVUS TRIAL : IVUS ANALYSISOLIVUS TRIAL : IVUS ANALYSIS

Representative Serial Volumetric IVUS Analysis in the Control Group(A) Baseline intravascular ultrasound (IVUS); (B) 14-month follow-up.

J Am Coll Cardiol 2010;55:976–82

OLASOLAS

• The OLAS study was performed to assess whether combination therapy with OLM/AML was beneficial for markers of metabolic dysfunction

J Hypertension 2008; 26 Suppl. 1: 331.

OLAS-RESULTSOLAS-RESULTS

* P<0.01, ** P<0.005, *** P<0.001, vs baseline.Martinez-Martin ICTHD 2008.

-7.9

-12.6

-19.3

-11.2

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Ch

an

ge

fro

m b

ase

lin

e B

P (

mm

Hg

)

***

**

OLM/AML 20/5Week 13

*

**

OLM/AML 20/5 or 40/10Week 26

* P<0.01, ** P<0.005, *** P<0.001, vs baseline.Martinez-Martin ICTHD 2008.

-7.9

-12.6

-19.3

-11.2

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Ch

an

ge

fro

m b

ase

lin

e B

P (

mm

Hg

)

***

**

OLM/AML 20/5Week 13

*

**

OLM/AML 20/5 or 40/10Week 26

-7.9

-12.6

-19.3

-11.2

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Ch

an

ge

fro

m b

ase

lin

e B

P (

mm

Hg

)

***

**

OLM/AML 20/5Week 13

OLM/AML 20/5Week 13

*

**

OLM/AML 20/5 or 40/10Week 26

OLM/AML 20/5 or 40/10Week 26

OLAS-CHANGE IN INFLAMMATORY MARKERSOLAS-CHANGE IN INFLAMMATORY MARKERS

*P<0.05 vs baseline †P<0.01 vs baseline.Martinez-Martin ICTHD 2008.

TNFα hsCRP ICAM-1 VCAM-1 IL6 IL8

-12.3

-15.7

-24.4

-15.5

-9.4

-16.9

-25

-20

-15

-10

-5

0

Ch

an

ge

fro

m b

ase

lin

e (

%)

*

*

*

†

*

*

*P<0.05 vs baseline †P<0.01 vs baseline.Martinez-Martin ICTHD 2008.

TNFα hsCRP ICAM-1 VCAM-1 IL6 IL8

-12.3

-15.7

-24.4

-15.5

-9.4

-16.9

-25

-20

-15

-10

-5

0

Ch

an

ge

fro

m b

ase

lin

e (

%)

*

*

*

†

*

*

TNFα hsCRP ICAM-1 VCAM-1 IL6 IL8

-12.3

-15.7

-24.4

-15.5

-9.4

-16.9

-25

-20

-15

-10

-5

0

Ch

an

ge

fro

m b

ase

lin

e (

%)

*

*

*

†

*

*

Change in inflammatory markers after 26 weeks’ treatment with olmesartan/amlodipine.

ARBS SLOW PROGRESSION OF KIDNEY DISEASE IN TYPE 2 ARBS SLOW PROGRESSION OF KIDNEY DISEASE IN TYPE 2 DIABETESDIABETES

Trial Patients (n) Treatment Duration Endpoint Risk reduction (all p≤0.05)

RENAAL DM, nephropathy (1513)

Losartan vs PBO

3.4 y Composite: 2x serum cr conc, ESRD, death

15% risk ↓ in comp endpoint

IDNT HTN, DM, nephropathy (1715)

Irbesartan vs amlodipine vs

PBO

2.6 y Composite: 2x serum cr conc, ESRD, death

24% risk ↓ comp endpoint

IRMA-2 HTN, DM, MA (590)

Irbesartan vs PBO

2 y Time to new-onset diabetic nephropathy

39–70% risk ↓

MARVAL DM, MA (332) Valsartan vs PBO

24 wk % Δ urinary baseline albumin excretion rate

44% risk ↓ with valsartan

LIFE ≥55 y + HTN, LVH (9193)

Losartan vs atenolol

4.8 y CVS death, MI or stroke, DM

Up to 25% risk ↓ of CVS endpoints, 25% risk ↓ of DM

DIRECT DM, retinopathy (1905)

Candestan vs PBO

4.7 y Progression of retinopathy

13% risk ↓in progression (ns),↑ regression

All studies reviewed by Kopyt NP. JAOA. 2005;105(4):207–15. except DIRECT, Sjolie AK, et al. Lancet. 2008;372:1361–3.

NEWER HF TRIALS

• EMPHASIS HF TRIAL

• ATMOSPHERE TRIAL

PARADIUM-HF

• PARADIGM-HF– SAFETY AND EFfiCACY OF LCZ696

COMPARED TO ENALAPRIL.– NEUTRAL ENDOPEPTIDASE INHIBITOR

ADDED TO AN ARB – AVOID THE SHORTCOMINGS OF

OVERTURE STUDY • LONGER HALF-LIFE• TWICE A DAY• ARB INSTEAD OF AN ACEI• LITTLE RISK OF ANGIOEDEMA

POINTS FOR DISCUSSION

• NEWER UNDERSTANDING IN THE RAAS• RECENT LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS

• FUTURE ADVANCES• CONCLUSION

AT2R AGONISTS: STIMULATING THE RAAS• MORE PRONOUNCED IN PATHOLOGICAL CONDITIONS WHERE AT2R DENSITY IS

INCREASED.

COMPOUND 21– SELECTIVE AT2R AGONIST– ORAL BIOAVAILABILITY OF 20–30%– ↑ SYSTOLIC AND DIASTOLIC FUNCTION AFTER MI IN RATS– ANTI-INFLAMMATORY AND ANTIAPOPTOTIC ACTION– ACUTE INFUSION OF ↓ BLOOD PRESSURE– INHIBITS NUCLEAR FACTOR KAPPA B, ACTIVATES PROTEIN PHOSPHATASES,

AND REDUCES THE EXPRESSION OF THE INFLAMMATORY CYTOKINES– POSSIBLE BENEFITS in MYOCARDIAL FIBROSIS, ATHEROSCLEROSIS,

MYOCARDIAL INFARCTION, OR MYOCARDITIS

PRO-RENIN

Preprorenin >>>prorenin >>> renin

sequential cleavage of the N-terminal 20 and 46 amino acids of preprorenin

kidney also releases unprocessed pro-renin via a constitutive pathway

prorenin accounts for about 70% to 90% of the immunoreactive renin

(PRO)RENIN RECEPTOR: NEW POSSIBILITIES

• ANGIOTENSIN- INDEPENDENT EFFECTS, CONTROLLED THROUGH THE BINDING OF RENIN TO THE NEWLY DISCOVERED (P)RR

• REDUCED NEPHROPATHY IN DIABETIC RATS, AND CARDIAC FIBROSIS IN HYPERTENSIVE RATS

• A NONPEPTIDE INHIBITOR OF (P)RR RAAS INHIBITION WITH SIMULTANEOUS BLOCKADE OF ANGIOTENSIN-INDEPENDENT PRORENIN EFFECTS

• PARTICULARLY BENEFICIAL IN HIGH-RISK PATIENTS

ACE 2 ACTIVATORSXNT

Ang-(1-7) FORMULATIONS

• UNFAVOURABLE PHARMACOKINETICS• SYNTHETIC MAS RECEPTOR AGONISTS- AVE 0991

CHYMASES INHIBITORS

• THIS STUDY SHOWED - CHYMASE INHIBITION (TEI-F00806) MAY PROTECT AGAINST ELEVATED INTRARENAL ANGIOTENSIN II LEVELS, OXIDATIVE STRESS, AND RENAL DYSFUNCTION IN DIABETES.

• CHYMASE OFFERS A NEW THERAPEUTIC TARGET FOR DIABETIC NEPHROPATHY

ANTIANGIOTENSIN VACCINES

• ANTI-ANGIOTENSIN I VACCINE---- PMD3117– SOME EVIDENCE FOR RAAS BLOCKADADE

• CYT006, – ANTI-ANGIOTENSIN II ANTIGENIC PEPTIDE CONJUGATED TO A

VIRUS-LIKE PARTICLE– LOWERED SBP BY UP TO 21 MMHG IN SPONTANEOUSLY HYPER

TENSIVE RATS AND – WAS WELL TOLERATED IN A PHASE I STUDY– MODEST BLOOD PRESSURE REDUCTION (9/4 MMHG) IN A PHASE

IIA STUDY

Tissot, A. C. et al. effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet 371, 821–827 (2008).

GENE-BASED THERAPIES

OVEREXPRESSION OF ACE2 AND AT2R DELIVERED IN VIRAL VECTORS REDUCED CARDIAC REMODELLING.

? SAFETY AND RELIABILITY

CONCLUSIONS

• THE SCIENCE AND ART OF OPTIMAL,EFFECTIVE AND PATIENT FRIENDLY “RASS INHIBITION” STRATEGIES ARE STILL EVOLVING

• WE SHOULD HOPE FOR BETTER AND SAFER MOLECULES THAN THE EXISTING ONES IN NEAR FUTURE