4. POINTS FOR DISCUSSION
• NEWER UNDERSTANDING IN THE RAAS
• RECENT LAND MARK TRIALS
• NEWER MOLECULES
• NEWER TRIALS
• FUTURE ADVANCES
• CONCLUSION
5.
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
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
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
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
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.
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
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).
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
Editor's Notes
Available from: URL:http://www.endocrinetoday.com/view.aspx?rid=50284. Accessed on 25 th march, 2010
The CHARM and VALIANT studies have substantially increased our knowledge on the role of ARBs in patients with HF and post-MI LV dysfunction. 1 Results from both studies support previous findings that ARBs are a good alternative to ACE inhibitors in the minority of patients who cannot tolerate ACE inhibitors, both after acute MI and in HF. ARBs consistently reduced HF hospitalizations in CHARM and VALIANT, as was also shown in Val-HeFT. Whereas no effect on all-cause mortality was demonstrated in either Val-HeFT or VALIANT, a reduction in CV mortality was shown in CHARM. 1 1. Voors AA, van Veldhuisen DJ. Role of angiotensin receptor blockers in patients with left ventricular dysfunction: Lessons from CHARM and VALIANT. Int J Cardiol. 2004;97:345-348.
This slide summarizes questions and answers before and after the CHARM and VALIANT studies about the role of ARBs in patients with LV dysfunction. 1 ARBs superior to ACE inhibitors? There is no evidence that ARBs are superior to ACE inhibitors, either in acute MI or HF; however when adequately dosed, ARBs may be equivalent to ACE inhibitors. ARBs non-inferior to ACE inhibitors? It is now well established that an ARB is a good alternative for the ACE inhibitor, both in CHF and in acute MI with signs of HF or LV dysfunction. ARBs additive on top of ACE inhibitors? VALIANT showed that in patients with acute MI, adding an ARB to an adequate-dose ACE inhibitor has no benefit. In contrast, CHARM showed that in patients with chronic HF, adding an ARB to an ACE inhibitor (and a beta-blocker) might reduce CV mortality. Moreover, a reduction in HF hospitalizations can be anticipated in both HF and after acute MI. Is the combination of ARB, ACE inhibitor, and beta-blocker dangerous? No, it is not. However, the benefits of triple therapy might be less pronounced following adequate and high doses of both the ACE inhibitor and beta-blocker. 1. Voors AA, van Veldhuisen DJ. Role of angiotensin receptor blockers in patients with left ventricular dysfunction: Lessons from CHARM and VALIANT. Int J Cardiol. 2004;97:345-348.
Clinical Overview of Benicar and Benicar HCT
There is strong evidence from outcomes studies that ARBs slow the progression of kidney disease in type 2 diabetes. Studies of patients with type 2 diabetes treated for various treatment periods with losartan, ibesartan ,or valsartan show risk reduction in CVS or renal endpoints. References Kopyt NP. Slowing progression along the renal disease continuum. JAOA. 2005;105(4):207–15. RENAAL: Brenner BM, et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9. IDNT: Lewis EJ, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60. IRMA-2: Parving HH, et al, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8. MARVAL: Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672 – 8. LIFE: Dahlöf B, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995 – 1003. DIRECT: Sjolie AK, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet. 2008;372:1361–3.