1) Blocking the renin-angiotensin-aldosterone system (RAAS) through ACE inhibitors or ARBs reduces oxidative stress, improves endothelial function, and lowers rates of atherosclerosis progression compared to other antihypertensives. 2) RAAS blockade improves glucose metabolism by increasing nitric oxide, reducing angiotensin II levels, and enhancing insulin sensitivity and glucose transport in skeletal muscle. Clinical trials show reduced cardiovascular events and nephropathy in diabetes patients treated with ACE inhibitors. 3) Multiple clinical trials demonstrate that targeting lower diastolic blood pressure goals or using RAAS blockade reduces cardiovascular events and new onset diabetes compared to other antihypertensive classes.

1. SRAA y Ateroesclerosis SRAA y Ateroesclerosis
drpp 2009 drpp 2009
Mecanismos de Inhibición del Bloqueo del SRAA y Stress Oxidativo
SRAA comparado con otros antihipertensivos
Valsartan Ramipril Doxazosin Metoprolol Amlodipine
80 mg od 5 mg od 4 mg od 100 mg od 10 mg od
(n = 20) (n = 20) (n = 20) (n = 22) (n = 20)
0
–10 –2.7% * –2.4% *
–20 –15.9% *
Aldosterone ! in MDA
blockers
Formation –30
(%) –40 *P <0.001 vs baseline.
–50
–60 –57.6%
–70
–67.2%*
Change from baseline in formation of malondialdehyde (MDA), a marker of lipid peroxidation, after 3
months treatment (N = 102).
drpp 2009 Baykal Y et al. J Hypertens. 2003;21:1207-1211. drpp 2009
Bloqueo de Receptor AT1 Efectos del Ramipril en la
Vasodilatación mediada por flujo Ateroesclerosis Carotídea
N=732 patients with vascular disease or diabetes
122 Hypertensive patients treated for 2 months
0.025 Mean Changes in BP:
2.0 RR -37 (P=0.028) Baseline to Study End
Mean Max. Carotid IMT Slope (mm/year)
1.66*
0.020 Systolic BP (mmHg)
1.5 1.32* Placebo: 0.1 ± 12.2
! 1.14* 0.015 Ramipril 2.5 mg/d: -4.6 ± 13.5*
FMD 1.0 Ramipril 10 mg/d: -4.1 ± 12.4*
(%)
0.010 Diastolic BP (mmHg)
0.5 Placebo: -0.4 ± 7.3
0.15 0.005 Ramipril 2.5 mg/d: -2.9 ± 7.9*
Ramipril 10 mg/d: -2.8 ± 7.6*
0.0
Placebo Losartan Irbesartan Candesartan 0
(n = 44) 100 mg 300 mg 16 mg Values are mean ± SD.
*P<0.001 for mean BP changes compared with
(n = 31) (n = 30) (n = 30) Placebo Ramipril Ramipril placebo. There were no significant differences in
*P < 0.05 vs baseline and vs placebo 2.5 mg 10 mg BP changes between the two active ramipril groups.
Referencia al. Am J Cardiol. 2004;93:1432-5.
Koh KK et drpp 2009 Lonn EM, et al. Circulation 2001; 103:919–25. drpp 2009

2. Val-PREST: Re-estenosis intra-Stent Mortalidad in SAVE,
y Reintervención a 6 meses TRACE, AIRE, y VALIANT
Valsartan 80 mg (n = 99)
Hazard Ratio for Mortality
Placebo (n = 101)
50
SAVE
50% reduction
with valsartan vs placebo
40
58% reduction
TRACE
with valsartan vs placebo
Restenosis (%)
Patients with
30
AIRE
*
20
* Combined
10
VALIANT
(imputed placebo)
0
0.5 1 2
Restenosis Reintervention
*P <0.005 vs placebo.
Favors Favors
Active Drug Placebo
Adapted with permission from Peters S et al. J Invasive Cardiol. 2001;13:93-97. drpp 2009 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 drpp 2009
MICRO-HOPE: IECAs Mejoran
Metas CV y Renales en Diabetes
N=3577 patients with diabetes
(SRAA) Sistema Overt
CV nephro-
Renina-Angiotensina-
MI Stroke death pathy Mean albumin:
0 creatinine ratio
3.0 Placebo
–10
2.5
Aldosterona:
Risk 2.0
Reduction –20 P=0.02
(%) 1.5 Ramipril 10 mg
1.0
Efectos Renales
–30 P=0.001
P=0.01
P=0.027 0.5
–40 0 1 2 3 4.5
P=0.007 Years
P=0.0001
drpp 2009 HOPE Study Investigators. Lancet. 2000;355:253–259. drpp 2009
(SRAA) Sistema
Renina-Angiotensina-
Aldosterona:
Diabetes
N Engl J Med.
www.mechanismsincardiology.com
2001;345:851-860. drpp 2009 drpp 2009

3. Bloqueo del SRAA y metabolismo de Bloqueo del SRAA: Mejoría del
glucosa: Insulina y mediadores Metabolismo de glucosa
BK
NO
Angiotensin I Bradykinin
BK2 +
Receptor "NO Glucose ACE/Kininase II
Transport
Akt1 Degradation
+ Angiotensin II
Insulin products
Receptor + +
+ GLUT-4
Insulin IRS-1 PI3-K
+ Trans-
location
SRAA Blockage
- GLUT-4
Biosynthesis $Angiotensin II "Bradykinin
- GLUT-4
AT1
Receptor
!Skeletal muscle "Nitric oxide
blood flow
Ang II !Glucose metabolism
Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171–9. drpp 2009 Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171–9. drpp 2009
Efecto de los IECA’s en Diabetes Metas de PA diastólica:
Estudio HOPE Estudio HOT
Reducción relativa del riesgo con Ramipril vs
Placebo en pacientes con Diabetes 30
-2.1 mmHg = -2.1 mmHg =
CV Events /1,000 Patient-Years in
Patients with Diabetes at Baseline
- 5.8 events/1000 py - 6.7 events/1000 py
25
22% de Infarto de Miocardio p = 0.01 20
33% de EVC p = 0.0074 15
37% de muerte cardiovascular p = 0.0001
24% de nefropatía p = 0.027 10
17% de revascularización p = 0.031
5
20% de Insuficiencia Cardíaca p = 0.019
0
Target: # 90 mmHg DBP # 85 mmHg DBP #80 mmHg DBP
(Achieved): (mean 85.2 mmHg) (mean 83.2 mmHg) (mean 81.1 mmHg)
p for trend = 0.005
HOPE investigators. Lancet 2000;355:253-259. drpp 2009 Referencia
Adapted from Hansson et al. Lancet 1998;351(9118):1755-1762. drpp 2009
Antihipertensivos: Prevención de Nuevos Casos de
Sensibilidad a la Insulina Diabetes tipo 2
Mejor Nuevo Mejor convencional
Estudio Seguimiento RR (IC 95%)
18 20 CAPPP (IECA vs Diu-BB) 6,1
16 0,86 (0,74-0,99); p= 0,03
12 HOPE (IECA vs Placebo)* 5,0 0,66 (0,51-0,85); p= 0,001
Cambio (%)
10
NORDIL (CA vs Diu-BB) 4,5 0,87 (0,73-1,04); p= 0,14
0 INVEST (CA vs BB) 2,7 0,85 (0,77-0,95); p= 0,01
-4
ALLHAT (IECA vs Diu) 4,6
-10 0,77 (0,66-0,89); p= 0,001
-15 LIFE (ARA II vs BB) 4,8
-22 -18 0,75 (0,63-0,88); p= 0,001
-30 -27 -20 CHARM (ARA II vs Placebo) 3,1
0,78 (0,64-0,96); p= 0,01
PRO
MET
-30
VALUE (ARA II vs CA) 4,2 0,77 (0,69-0,86); p= 0,0001
ATEN
HCTZ
NIF
VER
DOXA -40 0,50 0,75 1 1,25
IECA
ARA II
drpp 2009 drpp 2009

4. ARA II en Nefropatía Diabética
Referencia drpp 2009 Referencia drpp 2009