Transcript ARB - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

Journal Club
Harel Z, Gilbert C, Wald R, Bell C, Perl J, Juurlink D, Beyene J, Shah
PS.
The effect of combination treatment with aliskiren and blockers of the
renin-angiotensin system on hyperkalaemia and acute kidney injury:
systematic review and meta-analysis.
BMJ. 2012 Jan 9;344:e42. doi: 10.1136/bmj.e42.
2012年1月26日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
Ann Intern Med. 2003;138:593-602
Diagram of AⅡ signaling interactions with the insulin
receptor, IRS-1, and PI 3 kinase in RASMC
AⅡ
PI 3-kinase
P-Ser-
-Tyr-P
-Tyr-P
β
-Tyr-P
-Tyr-P
-Tyr-P
α
P-Ser-
Insulin
Receptor
P85
IRS-1
Folli et al: J. Clin. Invest. 100:2158–2169, 1997
P110
Insulin sensitivity after administration of ACE-I,
CaCB, and alpha AB
Insulin-medicated
glucose uptake,
glucose oxidation, and
non-oxidative glucose
disposal during the
euglycemic clamp
before (open bars) and
after (solid bars) 3
months of treatment
with doxazossin.
Giordano M, Matsuda M, Sanders L, Canessa ML, DeFronzo RA.: Effects of angiotensin-converting enzyme
inhibitors, Ca2+ channel antagonists, and alpha-adrenergic blockers on glucose and lipid metabolism in
NIDDM patients with hypertension. Diabetes. 1995 Jun;44(6):665-71.
Prevention of Diabetes Mellitus
follow-up,
year
drug
No. of new
on-set of DM
No.(total)
event
per 1000
person-years
control
antihypertensive drug
1999
CAPPP
6.1
ACEI
337
5183
10.7
β blocker
380
5230
11.9
1960
12.4
4.0
ACEI
93
1970
11.8
β blocker
Diuretic
CCB
97
STOP-2
95
1935
12.1
Trial
publication
1999
No. of new
No.(total)
on-set of DM
event
per 1000
person-years
HOPE
2001
4.5
ACEI
102
2837
8.0
Placebo
155
2883
11.9
ALLHAT
2002
4.0
ACE
119
4096
7.3
CCB
Diuretic
154
302
3954
6766
9.7
11.2
PEACE
ANBP-2
2004
4.8
ACEI
335
3432
20.3
Placebo
399
3472
23.9
2005
4.1
ACEI
138
2800
12.0
Diuretic
200
2826
17.3
AASK
2006
3.8
ACEI
45
410
28.9
β blocker
CCB
70
32
405
202
45.5
41.7
*DREAM
LIFE
*ALPINE
CHARM
SCOPE
VALUE
CASE-J
*ProFESS
*ONTARGET
2006
3.0
ACEI
449
2623
57.1
Placebo
489
2646
61.6
2002
4.8
ARB
242
4020
12.5
β blocker
320
3979
16.8
2003
1.0
ARB
1
196
5.1
Diuretic
8
196
40.8
2003
3.1
ARB
163
2715
19.4
Placebo
202
2721
23.9
2003
3.7
ARB
93
2167
11.6
Placebo
115
2175
14.3
2004
4.2
ARB
690
5087
32.3
CCB
845
5074
39.7
2007
3.2
ARB
38
1343
8.8
CCB
59
1342
13.7
2008
2.5
ARB
125
7306
6.8
Placebo
151
7283
8.3
2008
4.7
ARB
399
8542
10.0
ACEI
366
8576
9.2
*ONTARGET
2008
4.7
ARB
+ACEI
323
8502
8.1
ACEI
366
8576
9.2
*TRANSCEND
*HIJ-CREATE
*Kyoto Heart
*NAVIGATOR
2008
4.7
ARB
319
2954
26.4
Placebo
395
2972
28.8
2009
4.2
ARB
7
645
2.6
Placebo
18
624
6.9
2009
3.27
ARB+X
58
1116
51.6
X
86
998
76.7
2010
6.5
ARB
1532
3748
62.9
Placebo
1722
3725
71.1
Matsuda M.; Endocrinology＆Diabetology;26,1,35-41,2008.
Lancet. 2006 Oct 21;368(9545):1449-56.
Figure 1: The renin-angiotensin-aldosterone system
Black arrows show stimulation and red arrows show inhibition. Dotted lines show alternative pathways mainly documented in
experimental studies. β blockers, renin inhibitors, inhibitors of angiotensin-converting enzyme (ACE) and angiotensin II type-1
receptor blockers (ARB) reduce the activity of the renin-angiotensin system (RAS). AT-R=angiotensin receptor; EP=endopeptidases;
EC=endothelial cells.
Lancet. 2006 Oct 21;368(9545):1449-56.
Figure 2: Chemical structure of orally active renin inhibitors
Lancet. 2006 Oct 21;368(9545):1449-56.
Aliskiren is not metabolised by cytochrome P450, does not interfere with the
action of warfarin, and shows no clinically relevant pharmacokinetic
interactions with lovastatin, atenolol, celecoxib, or cimetidine.
Lancet. 2006 Oct 21;368(9545):1449-56.
Lancet. 2006 Oct 21;368(9545):1449-56.
Lancet. 2006 Oct 21;368(9545):1449-56.
Figure 3: The 24-hour systolic pressure at baseline and after inhibition of the renin system with either
aliskiren or losartan
Aliskiren and losartan were given for 4 weeks in once daily doses. of 150 mg (n=41), 300 mg (n=40) and 100 mg
(n=36), respectively. Adapted from reference 50 with permission from Lippincott Williams and Wilkins.
Objective
To examine the safety of using
aliskiren combined with agents
used to block the renin-angiotensin
system.
Design Systematic review and meta-analysis of
randomised controlled trials.
Data sources Medline, Embase, the Cochrane Library,
and two trial registries, published up to 7 May 2011.
Study selection Published and unpublished
randomised controlled trials that compared combined
treatment using aliskiren and angiotensin converting
enzyme inhibitors or angiotensin receptor blockers with
monotherapy using these agents for at least four weeks
and that provided numerical data on the adverse event
outcomes of hyperkalaemia and acute kidney injury. A
random effects model was used to calculate pooled risk
ratios and 95% confidence intervals for these outcomes.
Subgroup and sensitivity analysis
Planned subgroup analyses were not possible from
available data, and patient level data could not be
obtained. A retrospective sensitivity analysis was carried
out on the outcome severe hyperkalaemia, stratifying
patients by their risk of hyperkalaemia into low and high
risk groups (fig 5⇓). Seven studies enrolled patients at
high risk for hyperkalaemia (n=3141) and three enrolled
patients at low risk (n=1673). Meta-analysis found that
combination therapy did not significantly increase the
risk for severe hyperkalaemia in both groups: relative
risk in high risk patients 1.32 (95% confidence interval
0.64 to 2.74) and in low risk patients 0.42 (0.08 to 2.14).
Fig 2 Risk of hyperkalaemia among participants given combined aliskiren and
angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB) versus monotherapy (ACE inhibitor, ARB, or aliskiren). Values less than 1.0
indicate a decreased risk of outcome with combination therapy
Fig 3 Risk of acute kidney injury among participants given combined aliskiren and angiotensin converting enzyme (ACE) inhibitor or
angiotensin receptor blocker (ARB) versus monotherapy (ACE inhibitor, ARB, or aliskiren). Values less than 1.0 indicate a decreased
risk of outcome with combination therapy
Fig 4 Risk of hyperkalaemia stratified by severity among participants given combination therapy with aliskiren and angiotensin converting enzyme
(ACE) inhibitor or angiotensin receptor blocker (ARB) versus monotherapy with ACE inhibitor or ARB. Values less than 1.0 indicate a decreased risk
of outcome with combination therapy
Fig 5 Risk of severe hyperkalaemia stratified by high and low risk participants given combination therapy
with aliskiren and angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)
versus monotherapy with ACE inhibitor or ARB. Values less than 1.0 indicate a decreased risk of outcome
with combination therapy
Results
10 randomised controlled studies (4814
participants) were included in the analysis.
Combination therapy with aliskiren and
angiotensin converting enzyme inhibitors or
angiotensin receptor blockers significantly
increased the risk of hyperkalaemia compared
with monotherapy using angiotensin converting
enzymes or angiotensin receptor blockers
(relative risk 1.58, 95% confidence interval 1.24
to 2.02) or aliskiren alone (1.67, 1.01 to 2.79).
The risk of acute kidney injury did not differ
significantly between the combined therapy and
monotherapy groups (1.14, 0.68 to 1.89).
Conclusion
Use of aliskerin in combination with
angiotensin converting enzyme
inhibitors or angiotensin receptor
blockers is associated with an
increased risk for hyperkalaemia. The
combined use of these agents warrants
careful monitoring of serum potassium
levels.
Curr Vasc Pharmacol. 2012 Jan 13. [Epub ahead of print]
Aliskiren in Patients with Diabetes: A Systematic Review.
Rizos EC, Agouridis AP, Elisaf MS.
Source
Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina,
Greece. [email protected].
Abstract
Objective: Diabetic patients are at risk of macro- and micro-vascular complications,
including diabetic nephropathy, and have difficulties in achieving blood pressure (BP)
goals. Aliskiren, a direct renin inhibitor, inhibits the first step of the renin angiotensin
aldosterone system. We aimed to systematically address the relevant evidence on the
effects of aliskiren in diabetic individuals. Methods: We considered randomized
controlled trials (RCTs) evaluating aliskiren in diabetic patients. Information was
recorded independently by 2 investigators. We were limited to trials published in
English. Results: PubMed search retrieved 16 items. After excluding 12, we ended with
4 eligible studies with 1488 participants. Mean baseline BP levels were 143/82 mmHg
and median follow up was 2 months. Aliskiren was compared against angiotensin
converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) or aliskiren
plus ACE inhibitor/ARB in 2 studies and against placebo in the other 2. The most
frequent indication for aliskiren therapy was diabetes plus hypertension and
albuminuria. Aliskiren seems to be effective in reducing BP levels, albuminuria in
diabetics, either as monotherapy (compared with placebo), or in addition to ACE
inhibitors/ARB (compared with monotherapy), without any major safety considerations.
Conclusions: There are promising results on the effect of aliskiren in diabetic patients,
but the available evidence is limited so far. This is a poorly investigated field with few
RCTs and new studies focusing on "hard" outcomes are needed.
December 20, 2011
ALTITUDE was a multinational study in 8,606 patients
from 36 countries evaluating the potential benefits of
Rasilez/Tekturna to reduce the risk of cardiovascular
and renal events in this patient population.
ALTITUDE was the first randomized, double-blind,
placebo-controlled study to investigate
Rasilez/Tekturna for more than one year in a specific
population of patients with type 2 diabetes and renal
impairment. These patients are known to be at high
risk of cardiovascular and renal events. In the study,
Rasilez/Tekturna was given in addition to optimal
cardiovascular treatment including an angiotensin
converting enzyme (ACE) inhibitor or angiotensin
receptor blocker (ARB).
Message
AliskirenのRAS系への上乗せについて
と安全性を確認した論文。
高カリウム血症について問題
最近のALTITUDEの実際のデータは？
有効性