RENIN ANGIOTENSIN SYSTEM

1. RAAS INHIBITION
NEWER MOLECULES AND TRIALS

4. POINTS FOR DISCUSSION
• NEWER UNDERSTANDING IN THE RAAS
• RECENT LAND MARK TRIALS
• NEWER MOLECULES
• NEWER TRIALS
• FUTURE ADVANCES
• CONCLUSION

6. ANGIOTENSIN II – CENTRAL ROLE
High CV Risk
Post MI
Remodelling
Hypertension Ventricular dilation/
cognitive dysfunction
Myocardial
infarction &
Congestive heart failure/
stroke
secondary stroke
Heart Failure
Micro- Macro-
albuminuria proteinuria
Atherosclerosis End-stage
and LVH heart disease,
Endothelial Nephrotic brain damage
dysfunction proteinuria and dementia
End-stage Cardio/
Hypertension risk factors
renal cerebrovascular
diabetes, obesity, elderly
disease death
Adapted from Dzau V. and Braunwald E., Am Heart J 1991;121:1244–1263

7. CURRENT VIEW

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

9. POINTS FOR DISCUSSION
• NEWER UNDERSTANDING IN THE RAAS
• SOME LAND MARK TRIALS
• NEWER MOLECULES
• NEWER TRIALS
• FUTURE ADVANCES
• CONCLUSION

11. AT1-Receptor Blocker (ARB)
Clinical Outcome Studies
HBP VASCULAR MI HF
LIFE (ONTARGET) OPTIMAAL ELITE II
SCOPE (TRANSCEND) VALIANT Val-Heft
VALUE JIKEI
CHARM
(I-PRESERVE)
PRE-DIABETES DIABETES DIABETES RENAL
(NAVIGATOR) OPTHAL
(DIRECT) RENAAL
ATRIAL FIB IDNT
(ACTIVE)

12. Current Trial Programmes Cover the Largest
Population of CV High Risk Patients
High CV Risk
HOPE, EUROPA,
Post MI
PEACE, QUIET
SAVE AIRE; TRACE
ONTARGET
OPTIMAL,
TRANSCEND
VALIANT
PROfESS
Remodelling
Heart Failure
Ventricular dilation/ CHARM, ValHeFT
cognitive dysfunction
EPHESUS
Myocardial
Hypertension infarction &
Congestive heart failure/
LIFE etc stroke
secondary stroke
Micro- Macro-
73 million* albuminuria proteinuria
Atherosclerosis End-stage
and LVH heart disease,
Endothelial Nephrotic brain damage
dysfunction proteinuria and dementia
End-stage Cardio/
Hypertension risk factors
renal cerebrovascular
diabetes, obesity, elderly
disease death
Summary: Reduction of Neuroendocrine
Activation by Target Doses

13. Major Studies in RAS-Inhibition
0.25
(HOPE Composite)
Global Protection
0.20
HOPE Placebo ONTARGET
Ramipril
Telmisartan
0.15 Placebo Telmisartan/Ramipril
Ramipril
Telmisartan
0.10
TRANSCEND
0.05
0.00
0 360 720 1080 1440 1800 2160
Days of follow-up
AS-as7-0908

14. Major Studies in RAS-Inhibition
0.25
(HOPE Composite)
0.20
HOPE Placebo ONTARGET
Ramipril
Telmisartan
0.15 Placebo Telmisartan/Ramipril
Ramipril
Telmisartan
0.10
TRANSCEND
0.05
Unmet medical need
0.00
0 360 720 1080 1440 1800 2160
Days of follow-up
AS-as7-0908

15. RECENT Studies of Olmesartan in Diabetes

16. ROADMAP
(RANDOMISED OLMESARTAN AND DIABETES
MICROALBUMINURIA PREVENTION STUDY)

17. Benefit of ARB + ACE inhibitor in HF
HF hospitalization All-cause mortality
ARB+ ACEI ARB+ ACEI
ACEI better alone better ACEI better alone better
CHARM
(HF)
VALIANT
(post MI + HF/LV dysfunction)
Val-HeFT
(HF)
0.6 0.8 1.0 1.2 1.4 0.6 0.8 1.0 1.2 1.4
Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.

18. ARBs in LV dysfunction: Before/after
CHARM and VALIANT
Before After
CHARM, VALIANT CHARM, VALIANT
ARBs superior to ACEI? No (ELITE II, OPTIMAAL) No
ARBs non-inferior to ACEI? ? (ELITE II, OPTIMAAL) Yes
ARBs additive on top Yes, HF
of ACEI? ? (Val-HeFT) No, 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.

19. POINTS FOR DISCUSSION
• NEWER UNDERSTANDING IN THE RAAS
• SOME LAND MARK TRIALS
• NEWER MOLECULES
• NEWER TRIALS
• FUTURE ADVANCES
• CONCLUSION

20. 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)

21. NEWER RAS INHIBITORS ON THE WALL
Nat. Rev. Cardiol. 7, 431–441 (2010);

24. 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 .

25. ALISKIREN
 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

26. 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

27. ALSKIREN -TRAILS

28. ALSKIREN -TRAILS
ATMOSPHERE- ACUTE & CHRONIC CCF

29. 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);

30. ALDOSTERONE ANTAGONISM

31. 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

32. CALCIUM CHANNEL
BLOCKERS AS RAS
INHIBITORS

33. CALCIUM CHANNEL BLOCKERS

34. RECENT EVOLUTION OF DUAL AND
TRIPLE COMBINATIONS.

36. 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

37. POINTS FOR DISCUSSION
• NEWER UNDERSTANDING IN THE RAAS
• RECENT LAND MARK TRIALS
• NEWER MOLECULES
• NEWER TRIALS
• FUTURE ADVANCES
• CONCLUSION

38. 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
American Society of Nephrology Oct, 30th 2009

39. Impact of OLmesarten on
OLIVUS progression of
TRIAL coronary atherosclerosis:
evaluation by IntraVascular
Olivus study provides confirmation that UltraSound
Olmesartan can retard progression of
coronary atherosclerosis, the
underlying cause of heart disease
J Am Coll Cardiol 2010;55:976–82

40. OLIVUS 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

41. OLAS
• 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.

42. OLAS-RESULTS
OLM/AM 20/5
L OLM/AM 20/5 or 40/10
L
Change from baseline BP (mmHg)
Week 13 Week 26
0
-2
-4
-6
-8
-7.9
-10
*
-12 -11.2
-14 -12.6 **
**
-16
-18
-20 -19.3
***
* P<0.01, ** P<0.005, *** P<0.001, vs baseline.
Martinez-Martin ICTHD 2008.

43. OLAS-CHANGE IN INFLAMMATORY MARKERS
T Fα
N hsCRP ICAM-1 VCAM-1 IL6 IL8
0
Change from baseline (%)
-5
-10
-9.4
*
-12.3
-15 *
-15.7 -15.5
-16.9
* *
-20 *
-25 -24.4
†
*P<0.05 vs baseline †P<0.01 vs baseline.
Martinez-Martin ICTHD 2008.
Change in inflammatory markers after 26 weeks’ treatment with
olmesartan/amlodipine.

44. ARBS SLOW PROGRESSION OF KIDNEY DISEASE IN TYPE 2
DIABETES
Trial Patients (n) Treatment Duration Endpoint Risk reduction
(all p≤0.05)
RENAAL DM, Losartan vs 3.4 y Composite: 2x serum cr 15% risk ↓ in comp
nephropathy PBO conc, ESRD, death endpoint
(1513)
IDNT HTN, DM, Irbesartan vs 2.6 y Composite: 2x serum cr 24% risk ↓ comp
nephropathy amlodipine vs conc, ESRD, death endpoint
(1715) PBO
IRMA-2 HTN, DM, MA Irbesartan vs 2y Time to new-onset 39–70% risk ↓
(590) PBO diabetic nephropathy
MARVAL DM, MA (332) Valsartan vs 24 wk % Δ urinary baseline 44% risk ↓ with
PBO albumin excretion rate valsartan
LIFE ≥55 y + HTN, Losartan vs 4.8 y CVS death, MI or stroke, Up to 25% risk ↓ of
LVH (9193) atenolol DM CVS endpoints, 25%
risk ↓ of DM
DIRECT DM, Candestan vs 4.7 y Progression of 13% risk ↓in
retinopathy PBO retinopathy progression (ns),
(1905) ↑ regression
All studies reviewed by Kopyt NP. JAOA. 2005;105(4):207–15. except
DIRECT, Sjolie AK, et al. Lancet. 2008;372:1361–3.

45. NEWER HF TRIALS
• EMPHASIS HF TRIAL
• ATMOSPHERE TRIAL

46. 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

47. POINTS FOR DISCUSSION
• NEWER UNDERSTANDING IN THE RAAS
• RECENT LAND MARK TRIALS
• NEWER MOLECULES
• NEWER TRIALS
• FUTURE ADVANCES
• CONCLUSION

48. 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

49. 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

50. (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

51. ACE 2 ACTIVATORS
XNT

52. Ang-(1-7) FORMULATIONS
• UNFAVOURABLE PHARMACOKINETICS
• SYNTHETIC MAS RECEPTOR AGONISTS- AVE 0991

53. CHYMASES INHIBITORS

54. • 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

55. 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).

56. GENE-BASED THERAPIES
 OVEREXPRESSION OF ACE2 AND AT2R DELIVERED IN
VIRAL VECTORS REDUCED CARDIAC REMODELLING.
 ? SAFETY AND RELIABILITY

57. 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