1. Journal Club 2015年9月24日 8:30-8:55 ８階 医局
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: /NEJMoa
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

2. Meta-analysis of intensive glucose control in T2DM: major CV events including heart failure
Number of events
More intensive
Less intensive
Difference in HbA1c (%)
HR (95% CI)
Stroke
378
370
-0.88
0.96 (0.83, 1.10)
Myocardial infarction
730
745
0.85 (0.76, 0.94)
Hospitalisation for or death from heart failure
459
446
1.00 (0.86, 1.16)
Favours more intensive
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. Meta-analysis of intensive glucose control in T2DM: mortality
Number of events
More intensive
Less intensive
Difference in HbA1c (%)
HR (95% CI)
All-cause mortality
980
884
-0.88
1.04 (0.90,1.20)
CV death
497
441
1.10 (0.84,1.42)
Non-CV death
476
432
1.02 (0.89,1.18)
Favours more intensive
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

4. 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
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; SAVOR-TIMI 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: /eurheartj/ehv239

5. 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 EMPA-REG 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 non-fatal 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, September 2015

6. 埼玉医科大学総合医療センター　内分泌・糖尿病内科

7. N Engl J Med. September 17, 2015DOI: 10.1056/NEJMoa1504720
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: /NEJMoa

8. 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.

9. 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.

10. Participating countries
590 sites in 42 countries
Participating countries (42):
Argentina
Australia
Austria
Belgium
Brazil
Canada
Colombia
Croatia
Czech Republic
Denmark
Estonia
France
Georgia
Greece
Hong Kong
Hungary
India
Indonesia
Israel
Italy
Japan
Korea
Malaysia
Mexico
Netherlands
New Zealand
Norway
Peru
Philippines
Poland
Portugal
Romania
Russia
Singapore
South Africa
Spain
Sri Lanka
Taiwan
Thailand
Ukraine
United Kingdom
United States
North America, Australia, New Zealand
Latin America
Asia
Africa
Europe

11. Randomised and treated
Trial design
Placebo (n=2333)
Screening
(n=11531)
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

12. 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

13. 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

14. Baseline characteristics
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
Age, years
63.2 (8.8)
63.0 (8.6)
63.2 (8.6)
Male
1680 (72.0)
1653 (70.5)
1683 (71.9)
Region
Europe
959 (41.1)
966 (41.2)
960 (41.0)
North America*
462 (19.8)
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)
tlr-1245_0025final— Table : 1 Demographic data − treated set.
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
*Includes Australia and New Zealand

15. Baseline characteristics: type 2 diabetes
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
25 mg
(n=2342)
HbA1c, %
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)
Glucose-lowering medication*
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)
Insulin
1135 (48.6)
1132 (48.3)
1120 (47.8)
Mean daily dose, U**
65 (50.6)
65 (47.9)
66 (48.9)
Table : 1
Table : 5 but updated by MM (awaiting final PDF).
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

16. Baseline characteristics: CV risk factors
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%)
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)
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)
tlr-1245_0025final— Table : 1 Demographic data − treated set; Table : 4 Baseline efficacy and other variables − treated set.
tlr-1245_0025final— Table : 3 Descriptive statistics for SBP (mmHg) over time up to week 94 − treated set; Table : 3 Descriptive statistics for DBP (mmHg) over time up to week 94 − treated set.
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

17. Baseline characteristics: CV complications
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
Any CV risk factor
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%)
Cardiac failure*
244 (10.5%)
222 (9.5%)
tlr-1245_0025final— Table : 1 Baseline cardiovascular high risk factors − treated set
1245_0025final— Table : 3 Cardiac failure (narrow SMQ ) diagnosis at baseline − treated set
CAD defined as any of the components of history of MI, CABG, multivessel CAD, or single vessel CAD. Information on single vessel coronary artery disease was not available for one patient in the placebo group. Cardiac failure: based on narrow standardised MedDRA query ‘cardiac failure’.
Data are n (%) in patients treated with ≥1 dose of study drug
*Based on narrow standardised MedDRA query “cardiac failure”

18. Baseline characteristics: CV medication (1)
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
Anti-hypertensive therapy
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%)
1245_0025final— Table : 1 Anti−coagulants, lipid−lowering, antihypertensive and heart failure drugs at baseline − treated set
Data are n (%) in patients treated with ≥1 dose of study drug
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers

19. Baseline characteristics: CV medication (2)
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
Lipid-lowering drugs
1864 (79.9%)
1926 (82.1%)
1894 (80.9%)
Statins
1773 (76.0%)
1827 (77.9%)
1803 (77.0%)
Fibrates
199 (8.5%)
214 (9.1%)
217 (9.3%)
Ezetimibe
81 (3.5%)
95 (4.1%)
94 (4.0%)
Niacin
35 (1.5%)
56 (2.4%)
Other
175 (7.5%)
172 (7.3%)
193 (8.2%)
Anti-coagulants and anti-platelets
2090 (89.6%)
2098 (89.5%)
2064 (88.1%)
Acetylsalicylic acid
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%)
1245_0025final— Table : 1 Anti−coagulants, lipid−lowering, antihypertensive and heart failure drugs at baseline − treated set
Data are n (%) in patients treated with ≥1 dose of study drug

20. Exposure Placebo (n=2333) Empagliflozin 10 mg (n=2345)
Treatment duration, years
2.6 ( )
2.6 ( )
2.6 ( )
Observation time, years
3.1 ( )
3.2 ( )
Data are median (interquartile range) in patients treated with ≥1 dose of study drug
1245_0025final— Table : 1 Exposure to study drug − treated set; Table : 2 Overall observational period − treated set

21. HbA1c
1245_0025final study-report-body. Table : 1 HbA1c (%) change from baseline MMRM results over time − FAS (OC−AD) 12 28 40 52 66 80 94
108
122
136
150
164
178
192
206
Placebo
2294
2272
2188
2133
2113
2063
2008
1967
1741
1456
1241
1109
962
705
420
151
Empagliflozin 10 mg
2296
2272
2218
2150
2155
2108
2072
2058
1805
1520
1297
1164
1006
749
488
170
Empagliflozin 25 mg
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

22. Weight
Placebo
Empagliflozin 10 mg
1245_0025final study-report-body. Table : 1 Weight (kg) change from baseline MMRM results over time − treated set (OC−AD)
Empagliflozin 25 mg 12 28 52
108
164
220
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

23. Waist circumference
Placebo
Empagliflozin 10 mg
1245_0025final study-report-body. Table : 1 Waist circumference (cm) change from baseline MMRM results over time − treated set (OC−AD)
Empagliflozin 25 mg 12 28 52
108
164
220
Placebo
2259
1869
2183
2110
1562
1220
418
Empagliflozin 10 mg
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

24. Systolic blood pressure
Placebo
Empagliflozin 25 mg
1245_0025final study-report-body. Table : 1 SBP (mmHg) change from baseline MMRM results over time − treated set (OC−AD)
Empagliflozin 10 mg 16 28 40 52 66 80 94
108
122
136
150
164
178
192
206
Placebo
2322
2235
2203
2161
2133
2073
2024
1974
1771
1492
1274
1126
981
735
450
171
Empagliflozin 10 mg
2322
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. Diastolic blood pressure
Placebo
Empagliflozin 25 mg
1245_0025final study-report-body. Table : 1 DBP (mmHg) change from baseline MMRM results over time − treated set (OC−AD)
Empagliflozin 10 mg 16 28 40 52 66 80 94
108
122
136
150
164
178
192
206
Placebo
2322
2235
2203
2161
2133
2073
2024
1974
1771
1492
1274
1126
981
735
450
171
Empagliflozin 10 mg
2322
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

26. Heart rate (ECG)
Empagliflozin 10 mg
1245_0025final study-report-body (1). Table : 1 Heart rate (bpm) change from baseline MMRM results over time - treated set (OC-AD)
Placebo
Empagliflozin 25 mg 28 52 80
108
136
164
192
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

27. Low-density lipoprotein cholesterol
Placebo
1245_0025final study-report-body (1). Table : 1 LDL cholesterol (mg/dL) change from baseline MMRM results over time − treated set (OC−AD)
Empagliflozin 25 mg
Empagliflozin 10 mg 4 28 52 80
108
136
164
192
Placebo
2297
2273
2179
2104
2006
1932
1419
1086
694
Empagliflozin 10 mg
2294
2269
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

28. High-density lipoprotein cholesterol
Empagliflozin 25 mg
Empagliflozin 10 mg
Placebo
1245_0025final study-report-body (1). Table : 1 HDL cholesterol (mg/dL) change from baseline MMRM results over time − treated set (OC−AD) 4 28 52 80
108
136
164
192
Placebo
2297
2273
2181
2104
2007
1932
1419
1087
694
Empagliflozin 10 mg
2295
2270
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

29. Cardiovascular outcomes
Silvio E Inzucchi
Professor of Medicine, Yale University School of Medicine, New Haven, CT, USA

30. 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)

31. 3-point MACE Empagliflozin 10 mg HR 0.85 (95% CI 0.72, 1.01) p=0.0668
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio

32. 3-point MACE: sensitivity analyses
On-treatment analysis**
407/4607
227/2308
0.87
(0.74, 1.02)
0.0839
Per protocol analysis***
487/4654
278/2316
0.86
(0.75, 1.00)
0.0519
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
ITT: Table : 2
OS: Table : 1
PPS: Table : 3
Favours empagliflozin
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.

33. Patients with event/ analysed
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
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Favours empagliflozin
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

34. CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio

35. CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p=0.0016
Cumulative incidence function. HR, hazard ratio

36. Patients with event/analysed
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
1.24
(0.92, 1.67)
0.1638
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Favours empagliflozin
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

37. Fatal and non-fatal stroke
Patients with event/analysed
Empagliflozin
Placebo HR
(95% CI)
p-value
Intent-to-treat population
164/4687
69/2333
1.18
(0.89, 1.56)
0.2567
Numerical difference largely driven by events occurring >30 days after treatment stop
Favours empagliflozin
Favours placebo
Table : 2
On-treatment per protocol analysis (OS): Table : 3
On-treatment set (up to treat. stop + 30 days/indiv. trial compl): Table : 5
On-treatment analysis*
141/4607
66/2308
1.04
(0.78, 1.40)
0.7849
Favours empagliflozin
Favours placebo
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)

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)*
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
1.24
(0.92, 1.67)
0.1638
4-point MACE
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Favours empagliflozin
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 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
1.24
(0.92, 1.67)
0.1638
4-point MACE
599/4687
333/2333
0.89
(0.78, 1.01)*
0.0795
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Favours empagliflozin
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

40. 3-point MACE: subgroup analysis
HR (95% CI)
Empagliflozin
Placebo
All patients
4687
2333
Age, years
0.01
<65
2596
1297
≥65
2091
1036
Sex
0.81
Male
3336
1680
Female
1351
653
Race
0.09
White
3403
1678
Asian
1006
511
Black/African-American
237
120
HbA1c, %
<8.5
3212
1607
≥8.5
1475
726
Body mass index, kg/m2
0.06
<30
2279
1120
≥30
2408
1213
eGFR, mL/min/1.73m2
0.20
≥90
1050
488
60 to <90
2425
1238
<60
1212
607
p-value
for interaction
Favours empagliflozin
Favours placebo
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)

41. CV death: subgroup analyses
HR (95% CI)
Empagliflozin
Placebo
All patients
4687
2333
Age, years
0.21
<65
2596
1297
≥65
2091
1036
Sex
0.32
Male
3336
1680
Female
1351
653
Race
0.43
White
3403
1678
Asian
1006
511
Black/African-American
237
120
HbA1c, %
0.51
<8.5
3212
1607
≥8.5
1475
726
Body mass index, kg/m2
0.05
<30
2279
1120
≥30
2408
1213
eGFR, mL/min/1.73m2
0.15
≥90
1050
488
60 to <90
2425
1238
<60
1212
607
p-value
for interaction
Favours empagliflozin
Favours placebo
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)

42. Heart failure

43. Hospitalisation for heart failure
HR 0.65
(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio

44. 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

45. All-cause mortality

46. All-cause mortality HR 0.68 (95% CI 0.57, 0.82) p<0.0001
Kaplan-Meier estimate. HR, hazard ratio

47. All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87)
Kaplan-Meier estimate. HR, hazard ratio

48. 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)
Non-CV death
97/4687
57/2333
0.84
(0.60, 1.16)
0.2852
ACM: Table : 1
CV death: Table : 1
Non-CV death: Table : 3
Favours empagliflozin
Favours placebo
Cox regression analysis. CV, cardiovascular; HR, hazard ratio

49. Safety and tolerability
David Fitchett, MD
Cardiologist, St Michael’s Hospital Associate Professor of Medicine, University of Toronto, Toronto, Canada

50. Adverse events Placebo (n=2333) Empagliflozin 10 mg (n=2345)
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
tlr-1245_0025final— Table : 1 Demographic data − treated set.
Rate = per100 patient-years
*As reported by the investigator Patients treated with ≥1 dose of study drug

51. Adverse events consistent with urinary tract infection
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin
25 mg (n=2342)
n (%)
Rate
Events consistent with UTI
423 (18.1%)
8.21
426 (18.2%)
8.02
416 (17.8%)
7.75
Events leading to discontinuation 10
(0.4%)
0.17 22
(0.9%)
0.37 19
(0.8%)
0.31
By sex
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
Total: Table : 1
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
Based on 79 MedDRA preferred terms

52. Complicated urinary tract infection
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
n (%)
Rate
Complicated urinary tract infection*
41 (1.8%)
0.71
34 (1.4%)
0.57
48 (2.0%)
0.80
Urinary tract infection
16 (0.7%)
0.28
13 (0.6%)
0.22
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
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

53. Adverse events consistent with genital infection
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
n (%)
Rate
Events consistent with genital infection
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
By sex
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
Overall: table : 1
Serious: table : 4
Leading to discontinuation: table : 5
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug Based on 88 MedDRA preferred terms

54. Confirmed hypoglycaemic adverse events
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
n (%)
Confirmed hypoglycaemic adverse events
650 (27.9%)
656 (28.0%)
647 (27.6%)
Events requiring assistance
36 (1.5%)
33 (1.4%)
30 (1.3%)
Patients taking insulin at baseline
Total
483 (42.6%)
494 (43.6%)
464 (41.4%)
28 (2.5%)
27 (2.4%)
25 (2.2%)
Overall n(%): table : 4
Requiring assistance n (%): table : 4
Patients treated with ≥1 dose of study drug Plasma glucose <3.9 mmol/L (70 mg/dL) and/or requiring assistance

55. Other adverse events (1)
Placebo (n=2333)
Empagliflozin
10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
n (%)
Rate
Diabetic ketoacidosis* 1
(<0.1%)
0.02 3
(0.1%)
0.05
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
1.97
124
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 4
(0.2%)
0.07
Venous thrombotic events** 20
(0.9%)
0.35 9
(0.4%)
0.15 21
Table : 1 (tir), n(%)
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

56. Other adverse events (2)
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
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
1.57 87
(3.7%)
1.46
Table : 1 (tir), n(%)
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug *Based on standardised MedDRA queries †Based on 62 MedDRA preferred terms

57. Changes in clinical laboratory parameters
Electrolytes 
Sodium, mEq/L
141 (2)
0 (2)
Potassium, mEq/L
4.3 (0.4)
0.0 (0.4)
Calcium, mg/dL
9.7 (0.5)
0.0 (0.5)
9.7 (0.4)
Magnesium, mEq/L
1.7 (0.2)
0.0 (0.2)
0.1 (0.2)
Phosphate, mg/dL
3.7 (0.3)
0.0 (0.3)
0.1 (0.3)
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)
eGFR mL/min/1.73m2  
74.8 (20.6)
-4.5 (12.9)
75.2 (21.1)
-2.5 (13.1)
75.0 (21.4)
-2.8 (13.4)
Placebo (n=2333)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
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)
0.8 (1.3)
13.5 (1.5)
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

58. Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk 56
High CV risk
38% diabetes, 46% hypertension
Ramipril2
for 5 years
Empagliflozin
for 3 years 39
T2DM with high CV risk
92% hypertension
Simvastatin1
for 5.4 years 30
High CV risk
5% diabetes, 26% hypertension
All cause death
Simva: 182 / 2221 (8,2%), placebo :256 / 2223 (11,5%) HR= 0,71[0,59;0,85]
pooled empa : 269 (5.7%)/2333, placebo : 194 (8.3%)/ HR= 0.68 (0.57,0.82)
Ramipril: 482 / 4645 (10,4%), placebo : 569 / 4652 (12,2%) HR=0,85[0,76;0,95]
Pre-ACEi/ARB era
<29% statin
>80% ACEi/ARB
>75% statin
Pre-statin era
1994
2000
2015
1. 4S investigator. Lancet 1994; 344: , HOPE investigator N Engl J Med 2000;342:145-53,

59. 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 between-group 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.

60. 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, NCT )

61. 抄録 http://drmagician.exblog.jp/23687444/ 【背 景】
【背　景】
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 ; 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．

62. 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？