20150924EmpaReg - 埼玉医科大学総合医療センター内分泌

Journal Club
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S,
Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi
SE; EMPA-REG OUTCOME Investigators.
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2
Diabetes.
N Engl J Med. September 17, 2015DOI: 10.1056/NEJMoa1504720
2015年9月24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
Meta-analysis of intensive glucose control in
T2DM: major CV events including heart failure
Number of events
More
Less
intensive
intensive
Difference in
HbA1c (%)
HR (95% CI)
Stroke
378
370
-0.88
0.96 (0.83, 1.10)
Myocardial infarction
730
745
-0.88
0.85 (0.76, 0.94)
Hospitalisation for or
death from heart
failure
459
446
-0.88
1.00 (0.86, 1.16)
0.50
1.00
Favours more intensive
2.00
Favours less intensive
• Meta-analysis of 27,049 participants and 2370 major vascular events from:
– ADVANCE
– UKPDS
– ACCORD
– VADT
HR, hazard ratio; CV, cardiovascular
Turnbull FM et al. Diabetologia 2009;52:2288–2298
2
Meta-analysis of intensive glucose control in
T2DM: mortality
Number of events
More
Less
intensive
intensive
Difference in
HbA1c (%)
HR (95% CI)
All-cause mortality
980
884
-0.88
1.04 (0.90,1.20)
CV death
497
441
-0.88
1.10 (0.84,1.42)
Non-CV death
476
432
-0.88
1.02 (0.89,1.18)
0.50
1.00
Favours more intensive
2.00
Favours less intensive
• Meta-analysis of 27,049 participants and 2370 major vascular events from
– ADVANCE
– UKPDS
– ACCORD
– VADT
HR, hazard ratio; CV, cardiovascular
Turnbull FM et al. Diabetologia 2009;52:2288–2298
3
DPP4阻害薬、GLP-1受容体作動薬、SGLT2阻害薬の心血管障害への影響
1
1.
2.
2
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD,
Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVORTIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2
diabetes mellitus. N Engl J Med 2013;369:1317–1326.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR,
Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary
syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–1335.
European Heart Journal doi:10.1093/eurheartj/ehv239
Press Release Archive: Diabetes
20 August 2015
Jardiance® demonstrated cardiovascular (CV) risk reduction in people with type 2
diabetes at high risk for CV events
Ingelheim, Germany and Indianapolis, US, 20 August, 2015 – Boehringer Ingelheim
and Eli Lilly and Company today announced positive top-line results from EMPAREG OUTCOME®. This is a long-term clinical trial investigating cardiovascular
(CV) outcomes for Jardiance® (empagliflozin) in more than 7,000 adults with type
2 diabetes (T2D) at high risk for CV events. EMPA-REG OUTCOME® met its
primary endpoint and demonstrated superiority of Jardiance®, when added to
standard of care, in CV risk reduction. The primary endpoint was defined as time
to first occurrence of either CV death, or non-fatal myocardial infarction or nonfatal stroke.
Jardiance® is the only glucose-lowering agent to have demonstrated CV risk
reduction in a dedicated cardiovascular outcomes trial.
51st EASD Annual Meeting, Stockholm, Sweden, 14-18 September 2015
http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/20_august_2015_diabetes.html
累積処方患者数
ipragliflozin
dapagliflozin
luseogliflozin
tofogliflozin
canagliflozin
empagliflozin
合計
薬価収載
2014/4/17
2014/5/23
2014/5/23
2014/5/23
2014/9/3
2015/2/24
2014/6/30
2014/9/30
2014/12/31
2015/3/31
2015/8/27
43
5
0
0
0
0
62
17
6
0
0
0
78
17
9
4
3
0
92
18
9
4
3
0
135
58
16
5
2
0
48
85
111
126
216
埼玉医科大学総合医療センター内分泌・糖尿病内科
From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) and the Divisions of
Endocrinology (B.Z.) and Cardiology (D.F.), University of Toronto — all in Toronto; the Department
of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), Boehringer
Ingelheim Pharma, Biberach (E.B., S.H.), and Boehringer Ingelheim Pharma, Ingelheim (M.M.,
H.J.W., U.C.B.) — all in Germany; the Biostatistics Center, George Washington University, Rockville,
MD (J.M.L.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (T.D.); Boehringer Ingelheim
Norway, Asker, Norway (O.E.J.); and the Section of Endocrinology, Yale University School of
Medicine, New Haven, CT (S.E.I.).
N Engl J Med. September 17, 2015DOI: 10.1056/NEJMoa1504720
Background
The effects of empagliflozin, an inhibitor of
sodium–glucose cotransporter 2, in addition
to standard care, on cardiovascular
morbidity and mortality in patients with type
2 diabetes at high cardiovascular risk are
not known.
Methods
We randomly assigned patients to receive 10 mg
or 25 mg of empagliflozin or placebo once daily.
The primary composite outcome was death from
cardiovascular causes, nonfatal myocardial
infarction, or nonfatal stroke, as analyzed in the
pooled empagliflozin group versus the placebo
group. The key secondary composite outcome
was the primary outcome plus hospitalization for
unstable angina.
Participating countries
590 sites in 42 countries
Asia
North America, Australia, New Zealand
Latin America
Europe
Africa
10
Trial design
Screening
(n=11531)
Placebo
(n=2333)
Randomised
and treated
(n=7020)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
• Study medication was given in addition to standard of care
– Glucose-lowering therapy was to remain unchanged for first 12 weeks
• Treatment assignment double masked
• The trial was to continue until at least 691 patients
experienced an adjudicated primary outcome event
11
Key inclusion and exclusion criteria
• Key inclusion criteria
–
–
–
–
Adults with type 2 diabetes
BMI ≤45 kg/m2
HbA1c 7–10%*
Established cardiovascular disease
• Prior myocardial infarction, coronary artery disease, stroke, unstable
angina or occlusive peripheral arterial disease
• Key exclusion criteria
– eGFR <30 mL/min/1.73m2 (MDRD)
BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease
*No glucose-lowering therapy for ≥12 weeks prior to randomisation or no change in dose for ≥12 weeks prior to
randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation
12
Pre-specified primary and key secondary
outcomes
• Primary outcome
– 3-point MACE: Time to first occurrence of CV death, non-fatal
MI or non-fatal stroke
• Key secondary outcome
– 4-point MACE: Time to first occurrence of CV death, non-fatal
MI, non-fatal stroke or hospitalisation for unstable angina
CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event
13
Baseline characteristics
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
63.2 (8.8)
63.0 (8.6)
63.2 (8.6)
1680 (72.0)
1653 (70.5)
1683 (71.9)
Europe
959 (41.1)
966 (41.2)
960 (41.0)
North America*
462 (19.8)
466 (19.9)
466 (19.9)
Asia
450 (19.3)
447 (19.1)
450 (19.2)
Latin America
360 (15.4)
359 (15.3)
362 (15.5)
Africa
102 (4.4)
107 (4.6)
104 (4.4)
Age, years
Male
Region
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
*Includes Australia and New Zealand
14
Baseline characteristics: type 2 diabetes
HbA1c, %
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
8.08 (0.84)
8.07 (0.86)
8.06 (0.84)
Time since diagnosis of type 2 diabetes, years
≤5
423 (18.1)
406 (17.3)
434 (18.6)
>5 to 10
571 (24.5)
585 (24.9)
590 (25.2)
>10
1339 (57.4)
1354 (57.7)
1318 (56.3)
Metformin
1734 (74.3)
1729 (73.7)
1730 (73.9)
Sulphonylurea
992 (42.5)
985 (42.0)
1029 (43.9)
Thiazolidinedione
101 (4.3)
96 (4.1)
102 (4.4)
1135 (48.6)
1132 (48.3)
1120 (47.8)
65 (50.6)
65 (47.9)
66 (48.9)
Glucose-lowering medication*
Insulin
Mean daily dose, U**
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
*Medication taken alone or in combination
**Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg, n=1120
15
Baseline characteristics: CV risk factors
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
Body mass index, kg/m2
30.7 (5.2)
30.6 (5.2)
30.6 (5.3)
Weight, kg
86.6 (19.1)
85.9 (18.8)
86.5 (19.0)
Waist circumference, cm
105.0 (14.0)
104.7 (13.7)
104.8 (13.7)
Systolic blood pressure, mmHg
135.8 (17.2)
134.9 (16.8)
135.6 (17.0)
Diastolic blood pressure, mmHg
76.8 (10.1)
76.6 (9.8)
76.6 (9.7)
Heart rate, bpm*
70.7 (0.2)
71.0 (0.2)
70.5 (0.2)
LDL cholesterol, mg/dL
84.9 (35.3)
86.3 (36.7)
85.5 (35.2)
HDL cholesterol, mg/dL
44.0 (11.3)
44.7 (12.0)
44.5 (11.8)
eGFR, mL/min/1.73m2 (MDRD)
73.8 (21.1)
74.3 (21.8)
74.0 (21.4)
≥90 mL/min/1.73m2
488 (20.9%)
519 (22.1%)
531 (22.7%)
60 to <90 mL/min/1.73m2
1238 (53.1%)
1221 (52.1%)
1204 (51.4%)
<60 mL/min/1.73m2
607 (26.0%)
605 (25.8%)
607 (25.9%)
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
*Mean (SE). LDL, low density lipoprotein; HDL, high density lipoprotein; eGFR, estimated glomerular filtration
rate; MDRD, Modification of Diet in Renal Disease equation
16
Baseline characteristics: CV complications
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
2307 (98.9%)
2333 (99.5%)
2324 (99.2%)
Coronary artery disease
1763 (75.6%)
1782 (76.0%)
1763 (75.3%)
Multi-vessel coronary artery
disease
1100 (47.1%)
1078 (46.0%)
1101 (47.0%)
History of MI
1083 (46.4%)
1107 (47.2%)
1083 (46.2%)
Coronary artery bypass graft
563 (24.1%)
594 (25.3%)
581 (24.8%)
History of stroke
553 (23.7%)
535 (22.8%)
549 (23.4%)
Peripheral artery disease
479 (20.5%)
465 (19.8%)
517 (22.1%)
Single vessel coronary artery
disease
238 (10.2%)
258 (11.0%)
240 (10.2%)
244 (10.5%)
240 (10.2%)
222 (9.5%)
Any CV risk factor
Cardiac failure*
Data are n (%) in patients treated with ≥1 dose of study drug
*Based on narrow standardised MedDRA query “cardiac failure”
17
Baseline characteristics: CV medication (1)
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
2221 (95.2%)
2227 (95.0%)
2219 (94.7%)
ACE inhibitors/ARBs
1868 (80.1%)
1896 (80.9%)
1902 (81.2%)
Beta-blockers
1498 (64.2%)
1530 (65.2%)
1526 (65.2%)
Diuretics
988 (42.3%)
1036 (44.2%)
1011 (43.2%)
Calcium channel blockers
788 (33.8%)
781 (33.3%)
748 (31.9%)
Mineralocorticoid receptor
antagonists
136 (5.8%)
157 (6.7%)
148 (6.3%)
Renin inhibitors
19 (0.8%)
16 (0.7%)
11 (0.5%)
Other
191 (8.2%)
193 (8.2%)
190 (8.1%)
Anti-hypertensive therapy
Data are n (%) in patients treated with ≥1 dose of study drug
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers
18
Baseline characteristics: CV medication (2)
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
1864 (79.9%)
1926 (82.1%)
1894 (80.9%)
1773 (76.0%)
1827 (77.9%)
1803 (77.0%)
Fibrates
199 (8.5%)
214 (9.1%)
217 (9.3%)
Ezetimibe
81 (3.5%)
35 (1.5%)
95 (4.1%)
56 (2.4%)
94 (4.0%)
35 (1.5%)
175 (7.5%)
172 (7.3%)
193 (8.2%)
2090 (89.6%)
2098 (89.5%)
2064 (88.1%)
1927 (82.6%)
1939 (82.7%)
1937 (82.7%)
Clopidogrel
249 (10.7%)
253 (10.8%)
241 (10.3%)
Vitamin K antagonists
156 (6.7%)
141 (6.0%)
125 (5.3%)
Lipid-lowering drugs
Statins
Niacin
Other
Anti-coagulants and antiplatelets
Acetylsalicylic acid
Data are n (%) in patients treated with ≥1 dose of study drug
19
Exposure
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
Treatment duration, years
2.6 (1.8-3.4)
2.6 (1.9-3.4)
2.6 (2.0-3.4)
Observation time, years
3.1 (2.2-3.5)
3.2 (2.2-3.6)
3.2 (2.2-3.6)
Data are median (interquartile range) in patients treated with ≥1 dose of study drug
20
HbA1c
Adjusted mean (SE) HbA1c (%)
9.0
8.5
Placebo
8.0
Empagliflozin 10 mg
Empagliflozin 25 mg
7.5
7.0
6.5
6.0
0
12
28 40 52
66
80
94 108 122 136 150 164 178 192 206
Week
Placebo
2294 2272
Empagliflozin 10 mg
Empagliflozin 25 mg
705
420
151
2296 2272
2188 2133 2113 2063 2008 1967 1741 1456 1241 1109 962
2218 2150 2155 2108 2072 2058 1805 1520 1297 1164 1006
749
488
170
2296 2280
2212 2152 2150 2115 2080 2044 1842 1540 1327 1190 1043
795
498
195
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
21
Weight
Adjusted mean (SE) weight (kg)
90
88
86
Placebo
Empagliflozin 10 mg
84
Empagliflozin 25 mg
82
80
0
12
28
52
108
164
220
Week
Placebo
2285 1915
2215
2138
1598
1239
425
Empagliflozin 10 mg
2290 1893
2238
2174
1673
1298
483
Empagliflozin 25 mg
2283 1891
2226
2178
1678
1335
489
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
22
Waist circumference
Adjusted mean (SE) waist
circumference (cm)
107
106
Placebo
105
104
Empagliflozin 10 mg
103
Empagliflozin 25 mg
102
101
0
12
28
52
108
164
220
Week
Placebo
2183
2110
1562
1220
418
Empagliflozin 10 mg
2259 1869
2272 1836
2219
2155
1644
1285
475
Empagliflozin 25 mg
2273 1857
2209
2157
1648
1329
486
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
23
Systolic blood pressure
Adjusted mean (SE) systolic
blood pressure (mmHg)
145
143
141
139
137
Placebo
135
Empagliflozin 25 mg
Empagliflozin 10 mg
133
131
129
127
125
0
16 28 40 52
66
80
94 108 122 136 150 164 178 192 206
Week
Placebo 2322
735
450
171
Empagliflozin 10 mg 2322
2235 2203 2161 2133 2073 2024 1974 1771 1492 1274 1126 981
2250 2235 2193 2174 2125 2095 2072 1853 1556 1327 1189 1034
790
518
199
Empagliflozin 25 mg 2323
2247 2221 2197 2169 2129 2102 2066 1878 1571 1351 1212 1070
842
528
216
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
24
Diastolic blood pressure
Adjusted mean (SE) diastolic
blood pressure (mmHg)
80
79
78
77
76
Placebo
75
Empagliflozin 25 mg
Empagliflozin 10 mg
74
73
72
71
70
0
16 28 40 52
66
80
94 108 122 136 150 164 178 192 206
Week
Placebo 2322
735
450
171
Empagliflozin 10 mg 2322
2235 2203 2161 2133 2073 2024 1974 1771 1492 1274 1126 981
2250 2235 2193 2174 2125 2095 2072 1853 1556 1327 1189 1034
790
518
199
Empagliflozin 25 mg 2323
2247 2221 2197 2169 2129 2102 2066 1878 1571 1351 1212 1070
842
528
216
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
25
Heart rate (ECG)
75
74
Adjusted mean (SE)
heart rate (bpm)
73
72
71
70
Empagliflozin 10 mg
Placebo
Empagliflozin 25 mg
69
68
67
66
65
0
28
52
80
108
136
164
192
Week
Placebo
2174
2127
2032
1928
1796
1300
1002
552
Empagliflozin 10 mg
2205
2137
2064
2006
1877
1366
1045
597
Empagliflozin 25 mg
2192
2127
2066
2006
1907
1383
1086
633
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
26
Low-density lipoprotein cholesterol
100
Adjusted mean (SE)
LDL cholesterol (mg/dL)
98
96
94
92
90
Placebo
Empagliflozin 25 mg
Empagliflozin 10 mg
88
86
84
82
80
04
28
52
80
108
136
164
192
Week
Placebo 2297 2273
Empagliflozin 10 mg 2294 2269
2179
2104
2006
1932
1419
1086
694
2205
2143
2072
1998
1474
1133
740
Empagliflozin 25 mg 2287 2256
2188
2132
2060
2020
1503
1169
779
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
27
High-density lipoprotein cholesterol
50
Adjusted mean (SE)
HDL cholesterol (mg/dL)
49
48
47
46
Empagliflozin 25 mg
Empagliflozin 10 mg
45
Placebo
44
43
42
41
40
04
28
52
80
108
136
164
192
Week
Placebo 2297 2273
Empagliflozin 10 mg 2295 2270
2181
2104
2007
1932
1419
1087
694
2209
2144
2074
2001
1475
1134
741
Empagliflozin 25 mg 2289 2259
2191
2135
2064
2022
1507
1170
779
All patients (including those who discontinued study drug or initiated new therapies) were included in this
mixed model repeated measures analysis (intent-to-treat)
X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements
28
Cardiovascular outcomes
Silvio E Inzucchi
Professor of Medicine, Yale University
School of Medicine, New Haven, CT, USA
29
Primary outcome:
3-point MACE
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.0382*
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio.
* Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)
30
3-point MACE
Empagliflozin 10 mg
HR 0.85
(95% CI 0.72, 1.01)
p=0.0668
Empagliflozin 25 mg
HR 0.86
(95% CI 0.73, 1.02)
p=0.0865
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio
31
3-point MACE: sensitivity analyses
Patients with event/ analysed
Empagliflozin Placebo
HR
(95% CI)
p-value
Intent-to-treat population
490/4687
282/2333
0.86 (0.74, 0.99)*
0.0382
227/2308
0.87
(0.74, 1.02)
0.0839
278/2316
0.86
(0.75, 1.00)
0.0519
On-treatment analysis**
407/4607
Per protocol analysis***
487/4654
0.5
Favours empagliflozin
1.0
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio.
*95.02% CI.
**Excluding events >30 days after last intake of study drug and patients who received study drug for <30 days
(cumulative).
***Patients treated with ≥1 dose of study drug who did not have important protocol violations.
32
CV death, MI and stroke
Patients with event/ analysed
Empagliflozin
Placebo
3-point MACE
490/4687
HR
(95% CI)
p-value
282/2333 0.86 (0.74, 0.99)*
0.0382
CV death
0.25
0.50
Favours empagliflozin
1.00
2.00
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event;
HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
33
CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio
34
CV death
Empagliflozin 10 mg
HR 0.65
(95% CI 0.50, 0.85)
p=0.0016
Empagliflozin 25 mg
HR 0.59
(95% CI 0.45, 0.77)
p=0.0001
Cumulative incidence function. HR, hazard ratio
35
CV death, MI and stroke
Patients with event/analysed
Empagliflozin
Placebo
HR
(95% CI)
p-value
3-point MACE
490/4687 282/2333 0.86 (0.74, 0.99)*
0.0382
CV death
172/4687
137/2333 0.62 (0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333 0.87 (0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
0.1638
1.24 (0.92, 1.67)
0.25
0.50
Favours empagliflozin
1.00
2.00
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event;
HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
36
Fatal and non-fatal stroke
Patients with event/analysed
Empagliflozin Placebo
HR
(95% CI)
p-value
(0.89, 1.56)
0.2567
Intent-to-treat population
164/4687
69/2333
1.18
Numerical difference largely driven by events
occurring >30 days after treatment stop
0.5
1.0
Favours
empagliflozin
2.0
Favours
placebo
On-treatment analysis*
141/4607
66/2308
1.04
(0.78, 1.40)
0.7849
0.5
1.0
Favours
empagliflozin
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; *Excluding events
>30 days after last intake of study drug and patients who received study drug for <30 days (cumulative)
2.0
Favours
placebo
3-point MACE and 4-point MACE
Patients with event/analysed
Empagliflozin
Placebo
HR
(95% CI)
p-value
3-point MACE
490/4687 282/2333 0.86 (0.74, 0.99)*
0.0382
CV death
172/4687
137/2333 0.62 (0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333 0.87 (0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
0.1638
1.24 (0.92, 1.67)
4-point MACE
0.25
0.50
Favours empagliflozin
1.00
2.00
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event;
HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
38
3-point MACE and 4-point MACE
Patients with event/analysed
Empagliflozin
Placebo
HR
(95% CI)
p-value
3-point MACE
490/4687 282/2333 0.86 (0.74, 0.99)*
CV death
172/4687
137/2333 0.62 (0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333 0.87 (0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
1.24 (0.92, 1.67)
0.1638
4-point MACE
599/4687
333/2333 0.89 (0.78, 1.01)*
0.0795
0.25
0.50
Favours empagliflozin
0.0382
1.00
2.00
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event;
HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
39
3-point MACE: subgroup analysis
HR (95% CI)
Empagliflozin Placebo
All patients
Age, years
<65
≥65
Sex
Male
Female
Race
White
Asian
Black/African-American
HbA1c, %
<8.5
≥8.5
Body mass index, kg/m2
<30
≥30
eGFR, mL/min/1.73m2
≥90
60 to <90
<60
4687
p-value
for interaction
2333
0.01
2596
2091
1297
1036
0.81
3336
1351
1680
653
0.09
3403
1006
237
1678
511
120
0.01
3212
1475
1607
726
0.06
2279
2408
1120
1213
1050
2425
1212
488
1238
607
0.20
0.25
0.50
1.00
Favours empagliflozin
For the test of homogeneity of the treatment group difference among subgroups with no adjustment for
multiple tests. eGFR, estimated glomerular filtration rate (according to Modification of Diet in Renal Disease
equation)
2.00
4.00
Favours placebo
40
CV death: subgroup analyses
HR (95% CI)
Empagliflozin Placebo
All patients
Age, years
<65
≥65
Sex
Male
Female
Race
White
Asian
Black/African-American
HbA1c, %
<8.5
≥8.5
Body mass index, kg/m2
<30
≥30
eGFR, mL/min/1.73m2
≥90
60 to <90
<60
4687
p-value
for interaction
2333
0.21
2596
2091
1297
1036
0.32
3336
1351
1680
653
0.43
3403
1006
237
1678
511
120
0.51
3212
1475
1607
726
0.05
2279
2408
1120
1213
1050
2425
1212
488
1238
607
0.15
0.25
0.50
1.00
Favours empagliflozin
For the test of homogeneity of the treatment group difference among subgroups with no adjustment for
multiple tests. eGFR, estimated glomerular filtration rate (according to Modification of Diet in Renal Disease
equation)
2.00
4.00
Favours placebo
41
Heart failure
42
Hospitalisation for heart failure
HR 0.65
(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
43
Hospitalisation for heart failure
Empagliflozin 10 mg
HR 0.62
(95% CI 0.45, 0.86)
p=0.0044
Empagliflozin 25 mg
HR 0.68
(95% CI 0.50, 0.93)
p=0.0166
Cumulative incidence function. HR, hazard ratio
44
All-cause mortality
45
All-cause mortality
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
46
All-cause mortality
Empagliflozin 10 mg
HR 0.70
(95% CI 0.56, 0.87)
p=0.0013
Empagliflozin 25 mg
HR 0.67
(95% CI 0.54, 0.83)
HR 0.68
p=0.0003
(95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
47
All-cause mortality, CV death and non-CV death
Patients with event/analysed
Empagliflozin Placebo HR
95% CI
p-value
All-cause mortality
269/4687 194/2333
0.68
(0.57, 0.82)
<0.0001
CV death
172/4687 137/2333
0.62
(0.49, 0.77)
<0.0001
Non-CV death
97/4687
0.84
(0.60, 1.16)
0.2852
57/2333
0.25
0.50
Favours empagliflozin
1.00
2.00
Favours placebo
Cox regression analysis. CV, cardiovascular; HR, hazard ratio
48
Safety and tolerability
David Fitchett, MD
Cardiologist, St Michael’s Hospital
Associate Professor of Medicine, University of Toronto,
Toronto, Canada
49
Adverse events
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
One or more AEs
2139
(91.7%)
178.67
2112
(90.1%)
150.34
2118
(90.4%)
148.36
One or more drug-related*
AEs
549
(23.5%)
11.33
666
(28.4%)
14.15
643
(27.5%)
13.38
One or more AEs leading to
discontinuation
453
(19.4%)
8.26
416
(17.7%)
7.28
397
(17.0%)
6.89
One or more serious AEs
988
(42.3%)
22.34
876
(37.4%)
18.20
913
(39.0%)
19.39
Rate = per100 patient-years
*As reported by the investigator
Patients treated with ≥1 dose of study drug
50
Adverse events consistent with urinary tract
infection
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
423
(18.1%)
8.21
426
(18.2%)
8.02
416
(17.8%)
7.75
10
(0.4%)
0.17
22
(0.9%)
0.37
19
(0.8%)
0.31
Male
158
(9.4%)
3.96
180
(10.9%)
4.49
170
(10.1%)
4.09
Female
265
(40.6%)
22.81
246
(35.5%)
18.83
246
(37.3%)
20.38
Events consistent with UTI
Events leading to
discontinuation
By sex
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
Based on 79 MedDRA preferred terms
51
Complicated urinary tract infection
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
41
(1.8%)
0.71
34
(1.4%)
0.57
48
(2.0%)
0.80
16
(0.7%)
0.28
13
(0.6%)
0.22
16
(0.7%)
0.27
Pyelonephritis†
22
(0.9%)
0.38
15
(0.6%)
0.25
20
(0.9%)
0.33
Urosepsis
3
(0.1%)
0.05
6
(0.3%)
0.10
11
(0.5%)
0.18
Complicated urinary tract
infection*
Urinary tract infection
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
Events reported in >0.1% of patients in any group are shown
*Pyelonephritis, urosepsis or serious adverse event consistent with urinary tract infection
†Based on 15 MedDRA preferred terms
52
Adverse events consistent with genital infection
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
42
(1.8%)
0.73
153
(6.5%)
2.66
148
(6.3%)
2.55
Serious events
3
(0.1%)
0.05
5
(0.2%)
0.08
4
(0.2%)
0.07
Events leading to
discontinuation
2
(0.1%)
0.03
19
(0.8%)
0.32
14
(0.6%)
0.23
Male
25
(1.5%)
0.60
89
(5.4%)
2.16
77
(4.6%)
1.78
Female
17
(2.6%)
1.09
64
(9.2%)
3.93
71
(10.8%)
4.81
Events consistent with
genital infection
By sex
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
Based on 88 MedDRA preferred terms
53
Confirmed hypoglycaemic adverse events
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Confirmed hypoglycaemic
adverse events
Events requiring
assistance
650 (27.9%)
656 (28.0%)
647 (27.6%)
36 (1.5%)
33 (1.4%)
30 (1.3%)
483 (42.6%)
494 (43.6%)
464 (41.4%)
28 (2.5%)
27 (2.4%)
25 (2.2%)
Patients taking insulin at
baseline
Total
Events requiring
assistance
Patients treated with ≥1 dose of study drug
Plasma glucose <3.9 mmol/L (70 mg/dL) and/or requiring assistance
54
Other adverse events (1)
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
1
(<0.1%)
0.02
3
(0.1%)
0.05
1
(<0.1%)
0.02
Acute kidney injury†
155
(6.6%)
2.77
121
(5.2%)
2.07
125
(5.3%)
2.12
Events consistent with
volume depletion§
115
(4.9%)
2.04
115
(4.9%)
1.97
124
(5.3%)
2.11
Serious events
24
(1.0%)
0.42
19
(0.8%)
0.32
26
(1.1%)
0.43
Events leading to
discontinuation
7
(0.3%)
0.12
1
(<0.1%)
0.02
4
(0.2%)
0.07
20
(0.9%)
0.35
9
(0.4%)
0.15
21
(0.9%)
0.35
Diabetic ketoacidosis*
Venous thrombotic events**
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
*Based on 4 MedDRA preferred terms. †Based on 1 standardised MedDRA query
§Based on 8 MedDRA preferred terms. **Based on 1 standardised MedDRA query
55
Other adverse events (2)
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
Hepatic injury*
108
(4.6%)
1.91
80
(3.4%)
1.35
88
(3.8%)
1.48
Hypersensitivity*
197
(8.4%)
3.59
158
(6.7%)
2.75
181
(7.7%)
3.14
Bone fractures†
91
(3.9%)
1.61
92
(3.9%)
1.57
87
(3.7%)
1.46
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
*Based on standardised MedDRA queries
†Based on 62 MedDRA preferred terms
56
Changes in clinical laboratory parameters
Placebo
(n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Baseline
Change
from
baseline
Baseline
Change
from
baseline
Baseline
Change
from
baseline
Haematocrit, %
41.1 (5.7)
0.9 (4.7)
41.2 (5.6)
4.8 (5.5)
41.3 (5.7)
5.0 (5.3)
Haemoglobin, g/dL
13.4 (1.5)
-0.1 (1.2)
13.4 (1.5)
0.8 (1.3)
13.5 (1.5)
0.8 (1.3)
Serum creatinine, mg/dL 1.04 (0.24)
0.07 (0.25)
1.03 (0.23)
0.04 (0.2)
1.04 (0.25)
0.04 (0.19)
74.8 (20.6)
-4.5 (12.9)
75.2 (21.1)
-2.5 (13.1)
75.0 (21.4)
-2.8 (13.4)
Sodium, mEq/L
141 (2)
0 (2)
141 (2)
0 (2)
141 (2)
0 (2)
Potassium, mEq/L
4.3 (0.4)
0.0 (0.4)
4.3 (0.4)
0.0 (0.4)
4.3 (0.4)
0.0 (0.4)
Calcium, mg/dL
9.7 (0.5)
0.0 (0.5)
9.7 (0.4)
0.0 (0.5)
9.7 (0.4)
0.0 (0.5)
Magnesium, mEq/L
1.7 (0.2)
0.0 (0.2)
1.7 (0.2)
0.1 (0.2)
1.7 (0.2)
0.1 (0.2)
Phosphate, mg/dL
3.7 (0.3)
0.0 (0.3)
3.7 (0.3)
0.1 (0.3)
3.7 (0.3)
0.1 (0.3)
eGFR mL/min/1.73m2
Electrolytes
Data are mean (SD) in patients treated with ≥1 dose of study drug
Changes from baseline are at last value on treatment, defined as the last measurement ≤3 days after the
last intake of study drug
57
Number needed to treat (NNT) to prevent one death
across landmark trials in patients with high CV risk
Simvastatin1
for 5.4 years
High CV risk
5% diabetes, 26% hypertension
Pre-statin era
1994
Ramipril2
for 5 years
High CV risk
38% diabetes, 46% hypertension
Empagliflozin
for 3 years
T2DM with high CV risk
92% hypertension
Pre-ACEi/ARB era
>80% ACEi/ARB
<29% statin
>75% statin
2000
2015
1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm;
2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm
58
Results
A total of 7020 patients were treated (median observation time,
3.1 years). The primary outcome occurred in 490 of 4687 patients
(10.5%) in the pooled empagliflozin group and in 282 of 2333
patients (12.1%) in the placebo group (hazard ratio in the
empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to
0.99; P=0.04 for superiority). There were no significant betweengroup differences in the rates of myocardial infarction or stroke,
but in the empagliflozin group there were significantly lower rates
of death from cardiovascular causes (3.7%, vs. 5.9% in the
placebo group; 38% relative risk reduction), hospitalization for
heart failure (2.7% and 4.1%, respectively; 35% relative risk
reduction), and death from any cause (5.7% and 8.3%,
respectively; 32% relative risk reduction). There was no significant
between-group difference in the key secondary outcome (P=0.08
for superiority). Among patients receiving empagliflozin, there was
an increased rate of genital infection but no increase in other
adverse events.
Conclusions
Patients with type 2 diabetes at high risk for
cardiovascular events who received empagliflozin,
as compared with placebo, had a lower rate of
the primary composite cardiovascular outcome
and of death from any cause when the study drug
was added to standard care.
(Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG
OUTCOME ClinicalTrials.gov number, NCT01131676.)
【背
景】
抄録
心血管リスクの高い2型糖尿病患者での心血管罹患および死亡において，ナトリウム-グルコース
共役輸送体-2阻害薬（SGLT2阻害薬）のエンパグリフロジンの標準治療への上乗せ効果は知られて
いない．
【方
法】
患者は1日1回のエンパグリフロジンの10mg，25mgまたはプラセボに無作為に割り付けられた．主
要複合評価項目は，エンパグリフロジン群対プラセボ群でプールされた解析としての心血管死，
非致死的心筋梗塞，非致死的脳卒中とした．副次複合評価項目は，主要評価項目に不安定狭心症
による入院を追加したものとした．
【結
果】
計7020例の患者が治療を受けた（観察期間中央値3.1年）．主要評価項目はエンパグリフロジン群
で4687例中490例（10.5%），プラセボ群で2333例中282例（12.1%）であった（HR 0.86; 95.02%CI
0.74-0.99; p=0.04）．心筋梗塞や脳卒中の発生率は両群間で有意差はみられなかったが，エンパ
グリフロジン群で，心血管死亡率（3.7% vs 5.9%; 38%の相対リスク減少），心不全による入院率
（2.7% vs 4.1%; 35%の相対リスク減少），全死亡率（5.7% vs 8.3%; 32%の相対リスク減少）が
有意に低かった．両群間で副次評価項目に有意差はみられなかった（p=0.08）．エンパグリフロ
ジンを投与された患者において，生殖器感染症発生率の増加がみられたが，他の有害事象につい
ては有意差がみられなかった．
【結
論】
標準治療に試験薬を追加する設定において，エンパグリフロジンの投与を受けた，心血管イベン
トリスクの高い2型糖尿病患者は，プラセボ群と比較して，主要複合心血管評価項目と全死亡率が
低かった．
http://drmagician.exblog.jp/23687444/
Message
サブグループ解析で服薬でベネフィットのある集団は
 BMIは30未満
 年齢は65歳以上
 HbA1cは8.5%未満
 他の薬物(insulin, pioglitazone, DPP4阻害薬,metformin)
は用いていない
 蛋白尿は出ている
これまでよく言われている患者像とはかなり異なると感じる。
副作用関連では
 腎障害が減る
 尿路感染は特に女性で減る！
（性器感染は増えるが）
書いていないが、インスリンの減量効果、悪性腫瘍、脳梗塞既往のサブ解
析はどうか気にはかかるが？

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