Cardio Diabetes Master Class
Asian chapter
January 28-30 2011, Shanghai
Presentation topic
The expanding role of ARB’s in CV risk management:
Does it matter how we block the system?
Slide lecture prepared and held by:
Peter Meredith, PhD
University of Glasgow
Glasgow, United Kingdom
P H Y S I C IAN S ’ A CAD E M Y F O R CAR D I O VAS C U LAR E D U CAT I O N
The Renin Angiotensin System:
ACE Inhibition
ACE-independent
formation of ANG II
ACEI
Angiotensin I
ACE
Bradykinin
Angiotensin II
AT1
Vasoconstriction
Proliferation
Aldosterone
Sympathetic NS
NaCl-Retention
Inflammation
AT2
Antiproliferation
Differentiation
Regeneration
Anti-Inflammation
Apoptosis?
B2
NO, PGI2
Vasodilation, etc
NO
Vasodilation
Tissue protection
Apoptosis
Adapted from Unger & Stoppelhaar 2007
The Renin Angiotensin System:
AT1 Blockade
Angiotensin I
ACE
ARB
Angiotensin II
AT1
Vasoconstriction
Proliferation
Aldosterone
Sympathetic NS
NaCl-Retention
Inflammation
AT2
Antiproliferation
Differentiation
Regeneration
Anti-Inflammation
Apoptosis?
B2
NO, PGI2
Vasodilation, etc
NO
Vasodilation
Tissue protection
Apoptosis
Adapted from Unger & Stoppelhaar 2007
RAAS Blockade Across the CV Continuum
Vascular
Hypertension
• LIFE
• SCOPE
• VALUE
• KYOTO HEART
• CAPPP
• ANBP-2
• ALLHAT
• CASE-J
Heart Failure
• ELITE II
• Val-HeFT
• CHARM
• CONSENSUS I
• SOLVD
• PEP-CHF
• I-PRESERVE
• ELITE II
• Val-HeFT
• CHARM
• CONSENSUS I
• SOLVD
• PEP-CHF
• I-PRESERVE
Diabetes - Renal
• RENAAL
• IDNT
• ABCD-2V
• AASK
• MARVAL
• ADVANCE
• DETAIL
• DIRECT
• ROADMAP
Pre-Diabetes
• NAVIGATOR
• DREAM
MI
• OPTIMAAL
• VALIANT
• CONSENSUS II
• ISIS-4
• GISSI-3
• SMILE
• SAVE
• AIRE
• TRACE
CAD
• EUROPA
• PEACE
• IMAGINE
2o Stroke Prevention
• ACCESS
• PROGRESS
• PRoFESS
• SCAST
2007 ESH/ESC Guidelines: Choice of
Antihypertensive Drugs



The main benefits of antihypertensive therapy are due to lowering of
BP per se
Five major classes of antihypertensive agents – thiazide diuretics,
CCBs, ACE inhibitors, angiotensin receptor blockers (ARBs) and bblockers – are suitable for the initiation & maintenance of
antihypertensive treatment, alone or in combination. b-blockers,
especially in combination with a thiazide diuretic, should not be used in
patients with the metabolic syndrome or at high risk of incident
diabetes
Because in many patients more than one drug is needed, emphasis on
identification of the first class of drugs to be used is often futile.
Nevertheless, there are many conditions for which there is evidence in
favour of some drugs versus others either as initial treatment or as part
of a combination
January 2011
Presented at Cardio Diabetes Master Class Shanghai
Effect of Different Antihypertensives
on Incident Diabetes
results of a network meta-analysis of 22 clinical trials
ARB
0.57 (0.46, 0.72) p<0.0001
ACEI
0.67 90.56-0.80) p<0.0001
CCB
0.75 (0.62, 0.90) p=0.002
Placebo
0.77 (0.63, 0.94) p=0.009
b Blocker
0.90 (0.75, 1.09) p=0.30
Diuretic
Referent
0.5
1.25
0.7
0.9
Odds ratio of incident diabetes
Elliott & Meyer 2007
Regression of Left Ventricular Hypertrophy with
Antihypertensive Therapy by Drug Class
Mean % change in LV Mass from baseline (with 95% CI’s)
adjusted for change in diastolic BP & duration of treatment
* p<0.05; ** p<0.001 vs beta blocker
-5
-10
**
*
-15
-20
Diuretics
b-Blockers
*
change in LV Mass(%)
0
Calcium
ACE-Is
Antagonists
ARB’s
Klingbeil et al 2003
Quality of Life and Antihypertensive Treatment
Reported attitude
%
100
Improved
No change
Worse
80
60
40
20
0
Physician’s
opinion
Patient’s
opinion
Relative’s
opinion
Hosie & Wiklund 1995
Persistence with Antihypertensive Therapy
after 1 & 4 Years of Treatment
On treatment
%
AT1-blocker p<0.02 compared to all other classes
70
1 year
60
4 years
50
40
30
20
10
0
AT1-blocker
ACE-I
CCBs
Beta- blockers
Diuretics
Conlin et al 2001
ACEIs vs ARBs: Risk of Stroke
OR
(95%CI)
Events
ARBs ACEIs
ACEs v ACEIs
ELITE
1997
ELITE II
2000
OPTIMAAL
2002
DETAIL
2004
VALIANT (val)
2003
ONTARGET (tel)
2008
Fixed effect model (I2=0.0%, p=0.478)
Random effect model
1.41 (0.31,6.33)
1.64 (0.77,3.48)
1.06 (0.83,1.35)
1.09 (0.34,3.47)
0.85 (0.69,1.04)
0.91 (0.79,1.05)
4/352
3/370
18/1578
11/1574
140/2744
132/2733
6/120
6/130
180/4909
211/4909
369/8542
405/8576
717/18245
768/18292
0.93 (0.84, 1.03)
0.93 (0.90,1.03)
183/4885
211/4909
0.87 (0.71,1.06)
373/8502
405/8576
0.93 (0.80,1.07)
556/13387
616/13485
0.91 (0.81,1.02)
0.91 (0.81,1.02)
1273/31632
1384/31777
0.92 (0.85,0.99)
ARB + ACEs v ACEIs
VALIANT (val + cap)
ONTARGET (tel+ram)
2003
2008
Fixed effect model (I2=0.0%, p=0.602)
Random effect model
Overall Estimate
Fixed effect model (I2=0.0%, p=0.670)
Random effect model
0.92 (0.85,0.99)
favours 1st listed
heterogeneity between groups p=0.714
January 2011
Presented at Cardio Diabetes Master Class Shanghai
0.5
favours 2nd listed
1.0
Odds Ratio
2.0
ACEIs vs ARBs: Risk of Myocardial Infarction
ACEs v ACEIs
ELITE
ELITE II
OPTIMAAL
DETAIL
VALIANT (val)
ONTARGET (tel)
OR
(95%CI)
Events
ARBs ACEIs
1997
2000
2002
2004
2003
2008
Fixed effect model (I2=0.0%, p=0.884)
Random effect model
4/352
0.79 (0.17,3.54)
1.11 (0.66,1.85)
1.01 (0.87,1.18)
1.68 (0.58,4.86)
1.00 (0.90,1.11)
1.07 (0.94,1.23)
4/370
31/1578
28/1574
384/2744
379/2733
9/120
6/130
796/4909
798/4909
440/8542
413/8576
1663/18245
1628/18292
1.03 (0.95, 1.10)
1.03 (0.95,1.10)
ARB + ACEs v ACEIs
VALIANT (val + cap)
ONTARGET (tel+ram)
2003
2008
Fixed effect model (I2=0.0%, p=0.148)
Random effect model
756/4885
798/4909
0.94 (0.85,1.05)
438/8502
413/8576
1.07 (0.94,1.23)
1194/13387
1211/13485
0.99 (0.91,1.08)
1.00 (0.88,1.13)
2857/31632
2839/31777
1.01 (0.96,1.07)
Overall Estimate
Fixed effect model (I2=0.0%, p=0.759)
Random effect model
1.01 (0.96,1.07)
favours 1st listed
heterogeneity between groups p=0.555
January 2011
Presented at Cardio Diabetes Master Class Shanghai
0.5
favours 2nd listed
1.0
Odds Ratio
2.0
Antihypertensive Therapy & Type 2 Diabetes
•
•
•
optimal BP control with different classes of antihypertensives has
shown important benefits in reducing the risks of macrovascular
and microvascular disease
it has been suggested that antihypertensives that block the RAAS
might over additional benefit beyond BP control by way of delaying
the progression of diabetic nephropathy
whilst ACE Inhibitors have proven benefit in diminishing the
progression of nephropathy in type 1 diabetes, equivalent data in
type 2 diabetes is limited
January 2011
Presented at Cardio Diabetes Master Class Shanghai
AT1 Receptor Blockers in Type 2 Diabetes
IDNT (2001)
Irbesartan offers protection in hypertensive type 2 diabetics with nephropathy
Amlodipine only provided good BP control in diabetic patients
•
•
IRMA II (2001)
•
Irbesartan reduced the progression to nephropathy in hypertensive type 2
diabetics with microalbumiuria
RENAAL (2001)
Losartan delays ESRD and delays the decline in renal failure in hypertensive
type 2 diabetics with nephropathy
•
MARVAL (2001)
Vasartan was significantly more effective than amlodipine in reducing in
UAER type 2 diabetics with microalbuminuria
•
the renoprotective effects were independent of BP lowering
January 2011
Presented at Cardio Diabetes Master Class Shanghai
Comparison of Enalapril & Candesartan Cilexetil:
36 Hour ABPM after 8 Weeks Therapy
hours post dose
0
4
8 12 16 20 24 28 32 36
0
4
8 12 16 20 24 28 32 36
0
0
Diastolic ABP
Systolic ABP
-2
-4
-4
-8
-6
-12
-8
-10
-16
Candesartan 16 mg
Enalapril 20 mg
D SBP (mm Hg)
-12
D DBP (mm Hg)
EffECT Study Group
Chemical Structures of
Angiotensin II Receptor Blockers
O
CI
N
N
N
N
CO2H
S
N
N
N
N
COOH
N
NH
N
CO2H
N
NH
COOH
EXP 3174
Valsartan
Eprosartan
CH3
N
N
OCH2CH3
N
CO2H
N
N
N
N
NH
CH3
N
N
N
N
O
N
OH
CH3
Candesartan
January 2011
Presented at Cardio Diabetes Master Class Shanghai
Telmisartan
N
O
Irbesartan
N
NH
Antagonism of Angiotensin II-Induced Effects
by Candesartan and Losartan
Candesartan
125
Irbesartan
125
100
100
0.003nM
75
75
Control
10 nM
Control
0.03 nM
1 nM
50
50
25
25
0.1 M
1nM
0
0
-10
-9
-8
-7
-6
-5
Losartan
125
-10
-9
Control
50
10 nM
1 nM
0.1 M
0.1 nM
25
25
0
0
-10
-9
-8
-7
-6
-5
Control
75
50
-6
0.01 nM
100
75
-7
EXP-3174
125
100
-8
-5
-10
-9
-8
-7
-6
-5
Angiotensin II (nM)
Morsing et al 1998
Insurmountable and Surmountable Antagonism:
Relation to Duration of Binding
100
candesartan
Insurmountability (%)
80
telmisartan
olmesartan
EXP 3174
60
valsartan
40
irbesartan
20
losartan
0
0
20
40
60
Dissociation t1/2
80
100
120
Van Liefde et al 2009
Number of AT1-Receptor Binding Sites
for Different Angiotensin II Receptor Antagonists
2 sites - losartan
3 sites - valsartan
4 sites - candesartan
Hydrogen bonds between ligand and receptor are shown as red dotted
lines with hydrogen bond lengths. Carbon atoms of the ligands are
coloured light blue and those of the receptors are green
Bhuiyan et al 2009
Meta-Analysis Based on US
New Drug Application Evaluation Reports
-0
Reduction in diastolic BP (mmHg)
-2
Losartan
-4
Valsartan
Irbesartan
-6
Candesartan
0
0
0
0
25
80
75
4
50
160
150
8
100 mg
320 mg
300 mg
16 mg
Losartan
Valsartan
Irbesartan
Candesartan
Elmfeldt et al 2002
A Placebo Controlled ABPM Comparison of
Candesartan 8 mg and Losartan 50 mg
Systolic BP
Change in BP (mmHg)
4
Diastolic BP
2
0
0
-2
-4
-4
-8
*
-12
*
day
*p<0.001 vs placebo
#p<0.05 vs losartan
*
* night
-8
-10
*
*
-6
*#
*#
day
night
candesartan cilexetil 8 mg
losartan 50 mg
placebo
Mallion et al 1999
Candesartan Cilexetil vs Losartan : Mean Change From
Baseline to Week 8 in Systolic ABP
0
Hours after dose
12 14 16 18 20 22 24 26 28 30 32 34 36
-2
-4
-6
-8
Losartan 100mg
p=0.004
-10
-12
-14
-16
Candesartan cilexetil 16mg
-18
Change in SBP (mm Hg)
Lacourcière & Asmar 1999
Comparison of the Efficacy of Candesartan & Losartan:
Meta-Analysis of Trials in the Treatment of Hypertension
A systematic literature search of databases from 1980 to 1 October
2008 identified 13 studies in which candesartan and losartan (as monotherapy or in fixed combination with HCTZ) were compared in
randomised trials in hypertensive patients.
Data from 4066 patients were included in the statistical analysis which
was performed using RevMan software (v5), provided by the Cochrane
Information Management System using a random effect model.
Mean changes in SBP and DBP were compared for each drug alone
and after stratification for dose and for combination with HCTZ.
Meredith et al 2009
Candesartan & Losartan-Antihypertensive Effects:
Systolic BP in Direct Comparator Trials
Study or
Subgroup
Andersson et al 1998
Andersson et al 1998
Baguet et al 2006
Bakris et al 2001
Gradman et al 1999
Koenig et al 2000
Koh et al 2004
Lacourciere et al 1999
Lacourciere et al 1999
Manolis et al 2000
Matsuda et al 2003
Nishimura et al 2005
Ohman et al 2000
Rayner et al 2006
Vidtet al 2001
OVERALL
Candesartan
Mean SD Total
15.7
16.9
10.8
13.3
11.9
32.2
22.1
12.3
14.5
15.8
14.2
11.4
19.4
25.8
13.4
24.5
24.3
11.3
14.8
14.5
12.8
12.1
10.7
11.8
12.2
9.7
10
16.9
18.3
15.1
82
84
87
322
162
81
31
109
106
462
17
12
151
25
307
2038
Losartan
Mean SD Total
12.3
12.3
8.8
9.8
10
23.8
22.7
8.4
10.3
14.4
15.2
7.9
13.7
17.7
10.1
22.1
22.1
8.9
14.2
14.6
12.7
12.4
10.5
11.5
11.7
10.4
8.1
17.4
15.6
14.9
Weight
Mean Difference
95% CI
83
83
89
332
170
79
32
106
100
449
15
11
148
27
304
2.1%
2.1%
8.7%
12.6%
8.2%
5.8%
2.8%
9.4%
8.0%
17.5%
2.1%
1.9%
5.9%
1.3%
11.7%
3.40 [-3.72, 10.52]
4.60
4.60 [-2.44,
[-2.44, 11.64]
2.00 [-1.01, 5.01]
3.50 [1.28, 5.72]
1.90 [-1.23, 5.03]
8.40 [4.45, 12.35]
-0.60 [-6.65, 5.45]
3.90 [1.07, 6.73]
4.20 [1.02, 7.38]
1.40 [-0.15, 2.95]
-1.00 [-8.00, 6.00]
3.50 [-3.91, 10.91]
5.70 [1.81, 9.59]
8.10 [-1.18, 17.38]
3.30 [0.92, 5.68]
2028
100.0%
3.22 [2.16, 4.29]
Heterogeneity: Tau² = 1.06; Chi² = 19.19, df = 14 (P = 0.16); ²I = 27%
Test for overall effect: Z = 5.92 (P < 0.00001)
Favours Losartan
Favours Candesartan
-10
0
10
Mean Difference 95% CI
20
Meredith et al 2009
Candesartan & Losartan-Antihypertensive Effects:
Systolic BP in Direct Comparator Trials
Candesartan, n=
ALL TRIALS
2038
Mean Difference
95% CI
Losartan, n=
3.22 [2.16, 4.29]
2028
Heterogeneity: Tau² = 1.06; Chi² = 19.19, df = 14 (P = 0.16); I² = 27%
Test for overall effect: Z = 5.92 (P < 0.00001)
Monotherapy
1806
2.57 [1.71, 3.44]
1801
Heterogeneity: Tau² = 0.00; Chi² = 9.24, df = 12 (P = 0.68); I² = 0%
Test for overall effect: Z = 5.86 (P < 0.00001)
“Low Dose”
295
2.74 [0.83, 4.64]
293
Heterogeneity: Tau² = 0.00; Chi² = 2.01, df = 3 (P = 0.57); I² = 0%
Test for overall effect: Z = 2.81 (P < 0.005)
“High Dose”
1427
2.49 [1.52, 3.57]
1425
Heterogeneity: Tau² = 0.00; Chi² = 6.86, df = 7 (P = 0.44); I² = 0%
Test for overall effect: Z = 5.01 (P < 0.00001)
Favours Losartan
-10
Favours Candesartan
0
Mean Difference 95% CI
10
Meredith et al 2009
Candesartan & Losartan-Antihypertensive Effects:
Diastolic BP in Direct Comparator Trials
Candesartan Losartan
(n=)
(n=)
WMD
(mmHg)
95% CI
(mmHg)
Test of Overall Effect
Z=
p=
All Trials
2038
2028
2.21
1.34, 3.07
4.99
0.0001
Monotherapy
1806
1801
1.76
1.03, 2.50
4.70
0.0001
“Low-Dose”
295
293
2.02
0.81, 3.23
3.27
0.001
“High-Dose”
1427
1425
1.63
0.59, 2.67
3.06
0.002
232
227
4.34
0.82, 7.87
2.41
0.02
“HCTZ
Combination”
Meredith et al 2009
Potential Benefits of Additional BP Reductions
Meta-analysis of 61 cohort studies and 147 randomised trials suggests that in a 65 year old, monotherapy with a
standard dose of an antihypertensive, reduces diastolic BP by approximately 5mmHg resulting in:-
an additional 1.8 mmHg reduction in diastolic BP can be predicted to result in:-
% reduction in events
0
CHD
Stroke
-10
-20
-30
-40
Prospective Studies Collaboration 2002 & Law et al 2009
The Cardiovascular Continuum
ARB
Coronary Artery
Disease
Atherosclerosis
ARB
Endothelial Dysfunction
ARB
Plaque Rupture
Myocardial Infarction
Dilatation/Remodeling
ARB
Risk Factors
Heart Failure
Hypertension
Hyperlipidemia
Diabetes
End-Stage Heart Disease
ARB
Conclusions
 A volume of evidence suggests that tight blood pressure
control is of pivotal importance in optimising cardiovascular
outcome particularly in high risk groups
 Certain classes of antihypertensive appear to offer
additional benefit beyond blood pressure control
 Significant pharmacological differences with respect to
efficacy and duration of action are apparent within most
classes of antihypertensive
 For angiotensin receptor blockers these differences appear
to translate into important differences in CV outcome
January 2011
Presented at Cardio Diabetes Master Class Shanghai