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Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM.
Adverse cardiovascular events during treatment with pioglitazone and
rosiglitazone: population based cohort study.
BMJ. 2009 Aug 18;339:b2942. doi: 10.1136/bmj.b2942.
Takahisa Sawada1*, Hiroyuki Yamada1, Bjo¨ rn Dahlo¨ f 2, and Hiroaki
Matsubara1, for the KYOTO HEART Study Group
Effects of valsartan on morbidity and mortality in uncontrolled hypertensive
patients with high cardiovascular risks: KYOTO HEART Study
European Heart Journal doi:10.1093/eurheartj/ehp363
2009年10月１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
Effect of Rosiglitazone on the Risk of Myocardial Infarction
and Death from Cardiovascular Causes
Study
Rosiglitazone
Group
Control Group
Odds Ratio
（95% Cl）
P Value
no. of events / total no.（%）
Myocardial infarction
Small trials
combined
44 / 10,280（0.43）
22 / 6,105（0.36）
1.45（0.88-2.39）
0.15
DREAM
15 / 2,635（0.57）
9 / 2,634（0.34）
1.65（0.74-3.68）
0.22
ADOPT
27 / 1,456（1.85）
41 / 2,895（1.44）
1.33（0.80-2.21）
0.27
1.43（1.03-1.98）
0.03
Overall
Death from cardiovascular causes
Small trials
combined
25 / 6,557（0.38）
7 / 3,700（0.19）
2.40（1.17-4.91）
0.02
DREAM
12 / 2,365（0.51）
10 / 2,634（0.38）
1.20（0.52-2.78）
0.67
ADOPT
2 / 1,456（0.14）
5 / 2,854（0.18）
0.80（0.17-3.86）
0.78
1.64（0.98-2.74）
0.06
Overall
Nissen SE.:N Engl J Med.356.2007.May 21.Online
Assessment of the cardiovascular risks
and health benefits of rosiglitazone
David J. Graham, MD, MPH
Office of Surveillance and Epidemiology
Food and Drug Administration
July 30, 2007
Center for Drug Evaluation and Research
Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee
July 30, 2007
Does CV risk with RSG differ from that with PIO?
• Yes
•
From DREAM, relatively low-risk population:
RSG increased risk by ~40% c/w PBO
•
From PROactive, high risk population:
PIO decreased risk by ~15% c/w PBO
•
From RSG meta-analysis:
RSG increased risk of serious IHD by ~40% c/w all
comparators & by ~70% c/w PBO
•
From PIO meta-analysis:
PIO decreased risk by ~25% c/w all comparators
•
From head-to-head GLAI:
RSG increased risk 3.5-fold c/w PIO
Center for Drug Evaluation and Research
Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee
July 30, 2007
アクトスのイベントに及ぼす影響（メタ解析）
（%）
10
累
積
イ
ベ
ン
ト
発
症
率
総死亡、心筋梗塞、脳卒中
8
対照群
ピオグリタゾン群
6
4
ハザード比 95%信頼区間
2
ピオグリタゾン
vs 対照群
0.82
0.72,0.94
p値
0.005
0
0
症例数
7,836
対照群
アクトス群 8,554
20
40
60
80
100
120
6,470
6,556
5,509
5,370
4,133
4,026
3,735
3,679
3,534
3,505
2,826
2,810
140 （週）
2,143
2,146
19の臨床試験から16,390例を対象にピオグリタゾン群と対照群（プラセボ、SU薬、BG薬、インスリン）における、
イベントの発症率をメタ解析した。
Lincoff A.M. et al.:JAMA,298,1180,2007.
1Division
of Clinical Pharmacology and Toxicology, Department of Medicine,
Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada
M4N 3M5 2Department of Medicine, University of Toronto 3Department of Pediatrics,
University of Toronto 4Department of Health Policy, Management, and Evaluation,
University of Toronto 5Institute for Clinical Evaluative Sciences, Toronto 6Women’s
College Hospital, Toronto 7Department of Public Health Sciences, University of
Toronto 8Applied Health Research Centre, Li Ka Shing Knowledge Institute, St
Michael’s Hospital, Toronto
BMJ 2009;339:b2942
AIM
To compare the risk of acute
myocardial infarction, heart
failure, and death in patients
with type 2 diabetes treated
with rosiglitazone and
pioglitazone.
Method
Setting Ontario, Canada.
Participants Outpatients aged 66 years
and older who were started on
rosiglitazone or pioglitazone between 1
April 2002 and 31 March 2008.
Main outcome measure Composite of
death or hospital admission for either
acute myocardial infarction or heart
failure. In a secondary analysis, each
outcome was also examined individually.
Results
39 736 patients who started on either pioglitazone or
rosiglitazone were identified. During the six year study period,
the composite outcome was reached in 895 (5.3%) of patients
taking pioglitazone and 1563 (6.9%) of patients taking
rosiglitazone. After extensive adjustment for demographic
and clinical factors and drug doses, pioglitazone treated
patients had a lower risk of developing the primary outcome
than did patients treated with rosiglitazone (adjusted hazard
ratio 0.83, 95% confidence interval 0.76 to 0.90). Secondary
analyses revealed a lower risk of death (adjusted hazard ratio
0.86, 0.75 to 0.98) and heart failure (0.77, 0.69 to 0.87) with
pioglitazone but no significant difference in the risk of acute
myocardial infarction (0.95, 0.81 to 1.11). One additional
composite outcome would be predicted to occur annually for
every 93 patients treated with rosiglitazone rather than
pioglitazone.
Conclusion
Among older patients with diabetes,
pioglitazone is associated with a
significantly lower risk of heart
failure and death than is
rosiglitazone. Given that
rosiglitazone lacks a distinct clinical
advantage over pioglitazone,
continued use of rosiglitazone may
not be justified.
Message
Rosiglitazoneとpioglitazoneの比較では両者
の差が存在する。Pioglitazoneが有利であれば
rosiglitazoneを使う理由がない。
主要降圧薬の積極的適応
左室肥大
Ca拮抗薬
ARB/ACE阻害薬
●
●
心不全
●*1
心房細動（予防）
●
利尿薬
●
β遮断薬
●*1
頻脈
●*2
●
狭心症
●
●*3
心筋梗塞後
●
蛋白尿
●
腎不全
●
●*4
●
●
脳血管障害慢性期
●
糖尿病/MetS*5
高齢者
●
●
●*6
●
●
*1 少量から開始し、注意深く漸増する *2 非ジヒドロピリジン系Ca拮抗薬 *3 冠攣縮性狭心症には注意
*4 ループ利尿薬 *5 メタボリックシンドローム *6 ジヒドロピリジン系Ca拮抗薬
高血圧治療ガイドライン2009.
糖尿病を合併する高血圧の治療計画
治療開始血圧 130/80mmHg以上
生活習慣の修正・血糖管理と同時に薬物療法*
第一選択薬：ACE阻害薬、ARB
効果不十分
用量を増加
Ca拮抗薬、利尿薬を併用
効果不十分
3剤併用：ARBあるいはACE阻害薬、Ca拮抗薬、利尿薬
降圧目標 130/80mmHg未満
* 血圧が130-139/80-89mmHgで生活習慣の修正で降圧目標が見込める場合は、
3か月を超えない範囲で生活習慣の修正により降圧を図る
高血圧治療ガイドライン2009.
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
ARBの種類と糖尿病の発症
（２型糖尿病治療におけるARBの意義）
名称
投与薬
糖尿病の発症リスク (%) 比較対照薬
VALUE
ARB
-23
Ca拮抗薬
LIFE
ARB
-25
b遮断薬
ARB
-19
通常薬
(2004)
(2002)
SCOPE
(2002)
SHEP
利尿薬
(2005)
CAPPP
ACE阻害薬
HOPE
ACE阻害薬
(2004)
(2001)
INSIGHT
(2003)
Ca拮抗薬
偽薬
+49
-14
利尿薬/b遮断薬
偽薬
-34
-23
配合利尿薬
VALUE, LIFE, SCOPE, CHARMのメタ解析の発症リスクは-23%
NAVIGATOR, ONTARGET, TRANSCENDが進行中
糖尿病予防効果
ONTARGET 2008
ONTARGET 2008
4.7
4.7
ARB
399 8542 10.0
ARB+ACEI 323 8502 8.1
ACEI
ACEI
366
366
8576 9.2
8576 9.2
松田昌文：DREAM study 内分泌・糖尿病科 26(1):35-41, 2008.
JIKEI HEART 1
 従来治療群（Ca拮抗剤やACE阻害薬の増量・新規使用などによる）のサブ解析がされて
いない。
（解析中と思われるがCa拮抗剤、ACE阻害薬あるいは両方使用の３群の差を知りたい）
 バルサルタン群にはACE阻害薬がすでに投与されている患者も入っている。
従ってACEIとARBの併用という患者のバイアスがかかっていないか。
（参考）バルサルタン群とは
従来治療群にバルサルタンを追加投与する群
 従来治療群でACE阻害薬使用群と非使用群の比較検討は？
 CKD予防としてのARBの観点から腎不全進行抑制ができなかったのは不思議である。
（従来治療群にACE阻害薬が多く使われていて、そのために差が出なかった？）
 腎機能低下例でのサブ解析でACE阻害薬and/orARB群と非ACE阻害薬and/orARB群で
差が出るかも知れない。
（Solomon SD Circulation１１４;26：2006）
 患者数がスタートから終了時点で
バルサルタン群 １５４１例から３６８例
従来治療群
１５４０例から３４３例
に減少している。この減少数は一般的な数な
のか？
 http://blog.m3.com/reed/20070910/JIKEI__HEART_Study_2_
JIKEI HEART 2
http://rockymuku.sakura.ne.jp/zyunnkannkinaik
a/JIKEI%20HEART%20STUDY%20to%20PRO
BEhou.pdf
PROBEを用いた時は 「入院」のような介入方法
はエンドポイントにいれてはいけない。
Aim
The objective was to assess the
add-on effect of valsartan on top
of the conventional treatment for
high-risk hypertension in terms
of the morbidity and mortality.
Method
The KYOTO HEART Study was of a
multicentre, Prospective Randomised Open
Blinded Endpoint (PROBE) design, and the
primary endpoint was a composite of fatal and
non-fatal cardiovascular events (clintrials.gov
NCT00149227). A total of 3031 Japanese
patients (43% female, mean 66 years) with
uncontrolled hypertension were randomized
to either valsartan add-on or non-ARB
treatment.
Procedure
After confirming eligibility, patients were randomized in accordance with the
minimization method with eight factors (age, gender, dyslipidaemia, diabetes
mellitus, smoking, obesity, history of CAD and/or cerebrovascular disease, and
history of congestive heart failure), either to the valsartan add-on group or to the
conventional treatment group.
For the valsartan add-on group, valsartan 80 mg once daily in the morning was
administered to the patient as an initial dose, the dose was doubled after 4 weeks
if the initial dose could not achieve the target blood pressure of less than 140/ 90
mmHg (in patients with diabetes or renal disease, target blood pressure was set to
less than 130/80 mmHg).
After 8 weeks, an additional administration of other antihypertensive drugs with
flexible dosing regimen other than ARBs and ACE inhibitors was allowed if
necessary. Meanwhile, for the conventional treatment group, the antihypertensive
drugs other than ARB and ACE inhibitors were provided for the patients to
reach the target blood pressure.
The periodical follow-up was implemented every 6 months after setting the
sustainable dose.
Blood pressure at baseline was 157/88 and 133/76 mmHg at the end of study
stroke (hospitalization and diagnosed by CT and/or MRI), new or recurrent TIA (hospitalization and diagnosed by CT and/or
MRI and sudden onset of neurological deficit persisting for less than 24 h without the history of atrial arrhythmia that
causes embolism), new or recurrent acute myocardial infarction (hospitalization, ECGchange, and biomarkers for
myocardial infarction), new occurrence or exacerbation of angina pectoris (hospitalization and diagnosed by both ECG
changes corresponding with chest symptoms and coronary angiography showing .75% stenosis according to AHA/ACC
guidelines), new occurrence or exacerbation of heart failure (hospitalization and clinical symptoms together with left
ventricular dysfunction by echocardiography according to the guidelines of the AHA/ACC), dissecting aneurysm of the
aorta (hospitalization and diagnosed by imaging technique), lower limb arterial obstruction, emergency thrombosis,
transition to dialysis, and doubling of plasma Cr levels. The first of any of these events to occur in a specific patient was
classified as an event to be counted in the primary endpoint by the Endpoint Committee.
Results
Median follow-up period was 3.27 years.
In both groups, blood pressure at
baseline was 157/88 and 133/76 mmHg
at the end of study. Compared with
non-ARB arm, valsartan add-on arm
had fewer primary endpoints (83 vs.
155; HR 0.55, 95% CI 0.42–0.72, P .
0.00001).
Conclusion
Valsartan add-on treatment to improve
blood pressure control prevented more
cardiovascular events than
conventional non-ARB treatment in
high-risk hypertensive patients in
Japan. These benefits cannot be
entirely explained by a difference in
blood pressure control.
Message
PROBE法(まぁ色々問題点もあるが)で血圧が同じ
にもかかわらずvalsartanの優位性がしめされた。
糖尿病の発症も減少！（JIKEI HEARTはどうだったの？）