Transcript 20150611TECOS&VADTfollowUp

Journal Club
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R,
Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl
E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR; TECOS
Study Group.
Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.
N Engl J Med. 2015 Jun 8. doi: 10.1056/NEJMoa1501352
Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M,
Duckworth WC, Emanuele NV; VADT Investigators.
Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes.
N Engl J Med. 2015 Jun 4;372(23):2197-206. doi: 10.1056/NEJMoa1414266.
2015年6月11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
DPP-4阻害薬の心血管アウトカム試験
試験名
TECOS
EXAMINE
SAVOR-TIMI 53
CAROLINA
対象
2型糖尿病患者
急性冠症候群を合併 2型糖尿病患者
した2型糖尿病患者
2型糖尿病患者
薬剤名
シタグリプチン
アログリプチン
サクサグリプチン
リナグリプチン
対照薬
プラセボ
プラセボ
プラセボ
グリメピリド
登録例数
14,000例
5,400例
16,500例
6,000例
主要
エンドポイント
心血管死，非致死 心血管死，非致死的 心血管死，非致死
的心筋梗塞，非致 心筋梗塞，非致死的 的心筋梗塞，非致
死的脳卒中，不安 脳卒中の複合
死的虚血性脳卒中
狭心症による複合
の複合
心血管死，非致死
的心筋梗塞，非致
死的脳卒中，不安
狭心症による複合
観察期間
5年間
4.75年間
4年間
8.33年間
試験開始
2008年
2009年
2010年
2010年
試験終了予定
2014年12月
2013年12月
2013年7月
2018年9月
綿田裕孝（順天堂大学大学院代謝内分泌内科学）Pharma Medica ;30,8,157-164.2012.
clinicaltrials.gov（http://clinicaltrials.gov/）をもとに一部改変
N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684
SAVOR-TIMI53
BMI, HbA1c, FPG 推移
N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684
SAVOR-TIMI53
事前に設定された評価項目
No.[%]
主要評価項目:
心血管死、心筋梗塞、脳卒
中
副次評価項目：
主要評価項目
＋不安定狭心症による入院
心不全による入院
冠動脈血行再建述
総死亡
全ての心血管死
心筋梗塞
虚血性脳卒中
不安定狭心症による入院
心不全による入院
冠動脈血行再建術
血清クレアチニン倍化/血液透
析/腎移植/血清クレアチン
>6mg/dL
低血糖による入院
Saxagliptin
[N=8,280]
Placebo
[N=8,212]
ハザード比（95%
Cl）
P値
613[7.3]
609[7.2]
1.00（0.89~1.12）
0.99
1,059[12.8]
1,034[12.4]
1.02（0.94~1.11）
0.66
420[4.9]
269[3.2]
265[3.2]
157[1.9]
97[1.2]
289[3.5]
423[5.2]
378[4.2]
260[2.9]
278[3.4]
141[1.7]
81[1.0]
228[2.8]
459[5.6]
1.11（0.96~1.27）
1.03（0.87~1.22）
0.95（0.80~1.12）
1.11（0.88~1.39）
1.19（0.89~1.60）
1.27（1.07~1.51）
0.91（0.80~1.04）
0.15
0.72
0.52
0.38
0.24
0.007
0.18
194[2.2]
178[2.0]
1.08（0.88~1.32）
0.46
53[0.6]
Scirica
B.M. NEJM
published on Sep. 2, 2013.
1.22（0.82~1.83）
43[0.5]
0.33
HbA1cの推移
2
01
量ベ
ー
ス
ラ 1
イ
ン
か 0
ら
の
平
均 -1
変
化
-2
（%）
3
6
9
12
追跡期間
16（月）20
24
28
32
36
プラセボ（N=2,679）
アログリプチン
（N=2,701）
ベースラインHbA1C値
プラセボ: 8.03±1.11%
アログリプチン: 8.03±1.09%
Mean±SD
最終評価時におけるアログリプチン
と
プラセボとの差：
-0.36%; P<0.001
2,679 2,583 2,470 2,299 2,135 1,932
1,647
1,320
986
593
283
82
2,700 2,613 2,495 2,332 2,157 1,952
アログリプチン：
1,693
1,349
984
611
271
81
プラセボ：
White W.B. 欧州心臓会議（2013年9月2日、アムステルダム）
NEJM published on Sep. 2,
主要評価項目（心血管死、非致死性心筋梗塞、非致死性脳卒中）
ハザード比 0.96（信頼区間上限;
1.16）
1.3未満を達成（非劣性を証
（%）
24
イベント数
明）
（%）
プラセボ: 316（11.8）
アログリプチン: 305
（11.3）
累
積 18
イ
ベ
ン 12
ト
発
症
6
率
α（P）=0.01
プラセボ
アログリプチ
ン
0
0
6
2,679
アログリプチン：
2,701
プラセボ：
12
18
追跡期間（月）
24
30
2,299
1,891
1,375
805
286
2,316
1,899
1,394
821
296
White W.B. 欧州心臓会議（2013年9月2日、アムステルダム）
（例）
NEJM published on Sep. 2,
www.thelancet.com Published online March 10, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62225-X
www.thelancet.com Published online March 10, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62225-X
Duke Clinical Research Institute, Duke University School of Medicine, Durham (J.B.G., J.G., M.J.P., E.D.P.) and
University of North Carolina School of Medicine, Chapel Hill (J.B.B.) — both in North Carolina; Diabetes Trials Unit,
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom (M.A.B.,
R.R.H.); Canadian VIGOUR Centre, University of Alberta, Edmonton, AB (P.W.A.) and St. Michael’s Hospital,
University of Toronto, Toronto (R.J.) — both in Canada; Merck, Kenilworth, NJ (S.S.E., K.D.K., J.K., S.K., P.P.S.,
S.S.); George Washington University Biostatistics Center, Rockville, MD (J.M.L.); University of Texas
Southwestern Medical Center, Dallas (D.K.M.); Munich Diabetes Research Group, Helmholtz Center, Neuherberg,
Germany (E.S.); and University of Leuven, Leuven, Belgium (F.V.W.).
June 8, 2015 DOI: 10.1056/NEJMoa1501352
Background
Data are lacking on the long-term effect on
cardiovascular events of adding sitagliptin,
a dipeptidyl peptidase 4 inhibitor, to usual
care in patients with type 2 diabetes and
cardiovascular disease.
Methods
In this randomized, double-blind study, we
assigned 14,671 patients to add either sitagliptin
or placebo to their existing therapy. Open-label
use of antihyperglycemic therapy was
encouraged as required, aimed at reaching
individually appropriate glycemic targets in all
patients. To determine whether sitagliptin was
noninferior to placebo, we used a relative risk of
1.3 as the marginal upper boundary. The primary
cardiovascular outcome was a composite of
cardiovascular death, nonfatal myocardial
infarction, nonfatal stroke, or hospitalization for
unstable angina.
Figure 1.
Enrollment, Follow-up, and Vital Status.
GCP denotes Good Clinical Practice guidelines.
Figure 2. Glycated Hemoglobin Level.
Data are shown as mean values. The I bars indicate standard deviations.
Figure S1. Forest Plot of All Prespecified Subgroup Analyses for the Primary Composite Cardiovascular
Outcome.
Results
During a median follow-up of 3.0 years, there was a small
difference in glycated hemoglobin levels (least-squares
mean difference for sitagliptin vs. placebo, −0.29
percentage points; 95% confidence interval [CI], −0.32 to
−0.27). Overall, the primary outcome occurred in 839
patients in the sitagliptin group (11.4%; 4.06 per 100
person-years) and 851 patients in the placebo group
(11.6%; 4.17 per 100 person-years). Sitagliptin was
noninferior to placebo for the primary composite
cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88
to 1.09; P<0.001). Rates of hospitalization for heart failure
did not differ between the two groups (hazard ratio, 1.00;
95% CI, 0.83 to 1.20; P=0.98). There were no significant
between-group differences in rates of acute pancreatitis
(P=0.07) or pancreatic cancer (P=0.32).
Conclusions
Among patients with type 2 diabetes
and established cardiovascular disease,
adding sitagliptin to usual care did not
appear to increase the risk of major
adverse cardiovascular events,
hospitalization for heart failure, or other
adverse events.
(Funded by Merck Sharp & Dohme; TECOS
ClinicalTrials.gov number, NCT00790205.)
Message
単剤で比較した1つのRCTと、メトホルミン併用下で両
者を比較した2つのRCTの計3試験、2451人（シタグリプ
チン群1226人、SU薬群1225人）のデータを解析した。追
跡期間はメトホルミン併用下の1試験が30週、他の2試験
が104週であり、その間に発生した主要な心血管イベン
ト（MACE：Major Adverse CV Event）の発生率を比較し
た。
追跡期間内に発生したMACEは、シタグリプチン群が0
件、SU薬群が11件で、100人・年当たりの発生件数はそ
れぞれ0件、0.9件。心血管疾患による死亡件数は、シタ
グリプチン群0件、SU薬群5件で、100人・年当たりの発
生件数はそれぞれ0件、0.4件だった。
心不全について他と異なるのか？？？ HbA1cに差がない！
https://medical.nikkeibp.co.jp/leaf/all/gakkai/wdc2011/201112/522762.html
Changes in Median Glycated Hemoglobin Levels from
Baseline through 78 Months
VADT
Duckworth W et al. N Engl J Med 2009;360:129-139
Kaplan-Meier
Curves for the Time
until the First
Occurrence of a
Primary or
Secondary
Outcome
Duckworth W et al. N Engl J Med 2009;360:129-139
VADT ～イベント発症リスクと糖尿病罹病期間の関
係～
心
血
管
疾
患
発
症
に
お
け
る
ハ
ザ
ー
ド
比
強化療法の通常療法に対する
心血管疾患発症におけるハザード比
1.4
1.2
1.0
0.8
p＜0.0001
0.6
0.4
0
3
6
9
12
15
糖尿病罹病期間
18
21
24
（年）
2型糖尿病1,791例を無作為にロシグリタゾンを中心とした治療により強化療法群（HbA1C 6.0%未満）、または通常療法
（HbA1C 8.0～9.0%）に割り付けた。そして、主要心血管イベント（心血管死、心筋梗塞、脳卒中、うっ血性心不全、手術で
きない冠動脈疾患）、虚血部位の切断、冠動脈疾患へのインターベンション、末梢血管疾患を主要評価項目とした。
Duckworth W.：ADA 68th Scientific Sessions,2008,San Francisco.
Veterans Affairs (VA) Center for Clinical Management Research, VA Ann Arbor
Healthcare System, Ann Arbor, MI (R.A.H., W.L.W.); Phoenix VA Health Care
System, Phoenix, AZ (P.D.R., W.C.D.); and the Hines VA Cooperative Studies
Program Coordinating Center and Edward Hines, Jr., VA Hospital (G.D.B., D.J.R.,
L.G., N.V.E.), and VA Pharmacy Benefits Management Services (M.M.) — all in
Hines, IL.
N Engl J Med. 2015 Jun 4;372(23):2197-206. doi: 10.1056/NEJMoa1414266.
Background
The Veterans Affairs Diabetes Trial previously
showed that intensive glucose lowering, as
compared with standard therapy, did not
significantly reduce the rate of major
cardiovascular events among 1791 military
veterans (median follow-up, 5.6 years). We
report the extended follow-up of the study
participants.
Methods
After the conclusion of the clinical trial, we followed
participants, using central databases to identify
procedures, hospitalizations, and deaths (complete
cohort, with follow-up data for 92.4% of participants).
Most participants agreed to additional data collection
by means of annual surveys and periodic chart
reviews (survey cohort, with 77.7% follow-up). The
primary outcome was the time to the first major
cardiovascular event (heart attack, stroke, new or
worsening congestive heart failure, amputation for
ischemic gangrene, or cardiovascular-related death).
Secondary outcomes were cardiovascular mortality
and all-cause mortality.
* Plus–minus values are means ±SD.
Data are baseline values before
randomization. The group numbers are
participants who have complete followup data in the analyses (i.e., who were
followed until the end of December 2013,
had a primary-outcome event, or died
during active follow-up). The complete
cohort included follow-up data for 92.4%
of participants in the original trial. The
survey cohort included participants who
agreed to additional data collection by
means of annual surveys and periodic
chart reviews, with follow-up data for
77.7% of trial participants. The P values
are for the comparisons of the standardtherapy group with the intensive-therapy
group. There were no significant
differences between the complete cohort
and survey cohort in any of the above
characteristics. To convert the values for
weight to pounds, multiply by 2.2. To
convert the values for cholesterol to
millimoles per liter, multiply by 0.02586.
† Hypertension was defined as current
treatment for hypertension or a blood
pressure of 140/90 mm Hg or more.
‡ Race or ethnic group was self-reported.
§ The body-mass index is the weight in
kilograms divided by the square of the
height in meters.
¶ The estimated glomerular filtration rate
(GFR) was calculated with the use of the
Modification of Diet in Renal Disease
equation.
‖ The estimated 10-year cardiovascular
risk was calculated with the use of the
United Kingdom Prospective Diabetes
Study Risk Engine.19
Figure 2. Changes in Median Glycated Hemoglobin Level, According to Year since the Start of the Study.
Data are shown starting at year 3 because that was the point at which all the participants had been enrolled and
had been in the study for at least 3 months. The I bars (slightly offset for better visibility) represent interquartile
ranges. The vertical line represents the end of the interventional component of the trial and the beginning of the
follow-up study period. The reason for the slight decline in the difference in glycated hemoglobin levels between
the two groups that was observed in the last 6 months of the trial is unclear.
Figure 3. Probability Curves for Time to the
First Major Cardiovascular Event and for
Cardiovascular Mortality and Total Mortality.
The primary outcome was the time to the first
major cardiovascular event (a composite of
heart attack, stroke, new or worsening
congestive heart failure, amputation for
ischemic gangrene, or death from
cardiovascular causes).
Results
The difference in glycated hemoglobin levels between the
intensive-therapy group and the standard-therapy group
averaged 1.5 percentage points during the trial (median level,
6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points
by 3 years after the trial ended. Over a median follow-up of
9.8 years, the intensive-therapy group had a significantly
lower risk of the primary outcome than did the standardtherapy group (hazard ratio, 0.83; 95% confidence interval
[CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk
of 8.6 major cardiovascular events per 1000 person-years,
but did not have reduced cardiovascular mortality (hazard
ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in
total mortality was evident (hazard ratio in the intensivetherapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median
follow-up, 11.8 years).
Conclusions
After nearly 10 years of follow-up, patients
with type 2 diabetes who had been
randomly assigned to intensive glucose
control for 5.6 years had 8.6 fewer major
cardiovascular events per 1000 personyears than those assigned to standard
therapy, but no improvement was seen in
the rate of overall survival.
(Funded by the VA Cooperative Studies Program and
others; VADT ClinicalTrials.gov number, NCT00032487.)
Message
VADTでは罹病期間が長い場合に血糖の保護作用
がなかった。
全体的に見ても長期観察になると効果があるよ
うである。