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IntroductionBernard Zinman CM, MD, FRCP, FACP
Director, Leadership Sinai Centre for DiabetesProfessor of Medicine, University of Toronto
1
Disclosure
• Consultations and Honoraria – AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck,
Novo Nordisk, Sanofi, Takeda
• Grant Support– Boehringer Ingelheim, Novo Nordisk, Merck
2
CV death All-cause mortality0
1
2
3
Haza
rd r
ati
o (
95%
CI)
(d
iabete
s vs
no d
iabete
s)
Type 2 diabetes is increasingly prevalent• Globally, 387 million people
are living with diabetes1
3
• At least 68% of people >65 years with diabetes die of heart disease2
This will rise to 592 million by 20351
1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. Centers for Disease Control and Prevention 2011; 3. Seshasai et al. N Engl J Med 2011;364:829-41
Mortality risk associated with diabetes (n=820,900)3
Diabetes is associated with significant loss of life years
Seshasai et al. N Engl J Med 2011;364:829-41
4
.
0
7
6
5
4
3
2
1
040 50 60 70 80 90
Age (years)
Years
of
life lost
Men7
6
5
4
3
2
1
040 50 60 70 80 900
Age (years)
Women
Non-vascular deaths
Vascular deaths
On average, a 50-year-old individual with diabetes and no history of vascular disease will die 6 years earlier compared to someone without diabetes
0.50
Number of events
More intensive
Lessintensive
Difference in HbA1c
(%)
HR (95% CI)
Stroke 378 370 -0.880.96 (0.83,
1.10)
Myocardial infarction 730 745 -0.880.85 (0.76,
0.94)
Hospitalisation for or death from heart failure
459 446 -0.881.00 (0.86,
1.16)
Meta-analysis of intensive glucose control in T2DM: major CV events including heart failure
5
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, cardiovascularTurnbull FM et al. Diabetologia 2009;52:2288–2298
0.50
Number of events
More intensive
Lessintensive
Difference in HbA1c
(%)
HR (95% CI)
All-cause mortality 980 884 -0.881.04
(0.90,1.20)
CV death 497 441 -0.881.10
(0.84,1.42)
Non-CV death 476 432 -0.881.02
(0.89,1.18)
Meta-analysis of intensive glucose control in T2DM: mortality
6
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, cardiovascularTurnbull FM et al. Diabetologia 2009;52:2288–2298
Recent trials of newer glucose-lowering agents have been neutral on the primary CV outcome
7
SAVOR-TIMI 53
EXAMINE
HR: 1.0(95% CI: 0.89,
1.12)
HR: 0.96(95% CI: UL
≤1.16)
TECOSHR: 0.98
(95% CI: 0.88, 1.09)
EMPA-REG OUTCOME®
ELIXAHR: 1.02
(95% CI: 0.89, 1.17)
Empagliflozin
DPP-4 inhibitors*
Lixisenatide
CV, cardiovascular; HR, hazard ratio; DPP-4, dipeptidyl peptidase-4*Saxagliptin, alogliptin, sitagliptinAdapted from Johansen OE. World J Diabetes 2015;6:1092-96
2013 2014 2015
Empagliflozin
• Empagliflozin is a highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2) in the kidney
• Glucose reduction occurs by reducing renal glucose reabsorption and thus increasing urinary glucose excretion
• In patients with type 2 diabetes, empagliflozin leads to1:
– Significant reductions in HbA1c – Weight loss – Reductions in blood pressure without increases in heart
rate
8
1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93
Empagliflozin modulates several factors related to CV risk
Adapted from Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-1009
BPArterial stiffness
GlucoseInsulin
Albuminuria
Uric acid
Other
↑LDL-C↑HDL-C
Triglycerides
Oxidative stress
Sympathetic nervous system activity
WeightVisceral adiposity
EMPA-REG OUTCOME®
• Randomised, double-blind, placebo-controlled CV outcomes trial
• ObjectiveTo examine the long-term effects of empagliflozin versus placebo, in addition to standard of care, on CV morbidity and mortality in patients with type 2 diabetes and high risk of CV events
10
CV, cardiovascular
Trial design
John M Lachin, ScDProfessor of Biostatistics and Epidemiology, and Statistics, The George Washington University,
Rockville, USA
11
Disclosure
• Consultations– Boehringer Ingelheim, Merck and Co., Gilead, Janssen, Novartis,
AstraZeneca
12
Participating countries
North America, Australia, New Zealand
Latin America
Asia
Africa
Europe
590 sites in 42 countries
13
Trial design
• 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
14
Randomised and treated(n=7020)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
Placebo (n=2333)
Screening(n=11531)
Timeline
• September 15th 2010: First patient entered
• April 13th 2013: Last patient entered
• December 15th 2014: Closeout (final visits) started
• April 13th 2015: Last patient out
• Efforts were made to track outcomes and vital status for all patients, including those who discontinued trial medication
15
Patient disposition
Placebo Empagliflozin 10 mg
Empagliflozin
25 mg
N (%)
Intent-to-treat population 2333 (100) 2345 (100) 2342 (100)
Discontinued study drug prematurely
683 (29.3) 555 (23.7) 542 (23.1)
Completed study or died 2266 (97.1) 2264 (96.5) 2264 (96.5)
Vital status available 2316 (99.3) 2324 (99.1) 2327 (99.4)
16
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)
17
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
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
18
CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event
CV, cardiovascular; MI, myocardial infarction
Further pre-specified outcomes
• CV death• Non-fatal MI• Non-fatal stroke• Hospitalisation for heart failure• All-cause mortality
• All CV and neurological events were adjudicated by independent, masked, clinical event committees
19
Additional analyses
• Changes from baseline in:– HbA1c– Weight– Waist circumference– Systolic and diastolic blood pressure– Heart rate– LDL cholesterol– HDL cholesterol
• Safety and tolerability – Adverse events
20
HDL, high density lipoprotein; LDL, low density lipoprotein
Statistical testing strategy for MACE
• Analysis compared empagliflozin 10 mg and 25 mg (pooled) versus placebo
• Hierarchy to be used:
1. Test of non-inferiority for 3-point MACE
2. Test of non-inferiority for 4-point MACE
3. Test of superiority for 3-point MACE
4. Test of superiority for 4-point MACE • Each tested at =0.0249, allowing for 0.0001 penalty for
inclusion of interim data in NDA to FDA• Non-inferiority was concluded if two-sided upper bound of
95.02% CI was <1.3• Superiority was concluded if two-sided p≤0.0498
21
MACE; Major Adverse Cardiovascular Event; NDA, New Drug Application; FDA, Food and Drug Administration
Statistical analysis
• Analyses of CV outcomes were based on a Cox proportional hazards model
• Patients who did not have an event were censored on the last day they were known to be free of the outcome
• Cumulative incidence functions were corrected for mortality as a competing risk (except for all-cause mortality)
• The primary analysis was conducted in patients treated with ≥1 dose of study drug (intent-to-treat population)
• The CV outcome analyses were independently validated by statisticians at the University of Freiburg, Germany
22
Further pre-defined analyses of the primary outcome
• Secondary analyses: – Comparisons of empagliflozin 10 mg versus placebo
and empagliflozin 25 mg versus placebo
• Sensitivity analyses:– To assess the robustness of the outcomes, we used
three subsets of the data set (two on-treatment sets and one per-protocol set)
• Subgroup analyses based on baseline characteristics
23
Baseline characteristics and effectiveness results
Christoph Wanner, MDProfessor of Medicine, Division of Nephrology,
Würzburg University Clinic, Würzburg, Germany
24
Disclosures
• Grants from European Foundation of Studies in Diabetes– EFSD/Boehringer Ingelheim European Diabetes Research
Programme
25
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) 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)
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
26
*Includes Australia and New Zealand
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)
Placebo (n=2333)
Empagliflozin10 mg
(n=2345)
Empagliflozin25 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)
Baseline characteristics: type 2 diabetes
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
27
*Medication taken alone or in combination**Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg, n=1120
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%)
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)
Baseline characteristics: CV risk factors
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
28
*Mean (SE). LDL, low density lipoprotein; HDL, high density lipoprotein; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease equation
Baseline characteristics: CV complicationsPlacebo (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%) 240 (10.2%) 222 (9.5%)Data are n (%) in patients treated with ≥1 dose of study drug
29
*Based on narrow standardised MedDRA query “cardiac failure”
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers
Baseline characteristics: CV medication (1)
30
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%)
Data are n (%) in patients treated with ≥1 dose of study drug
Baseline characteristics: CV medication (2)
31
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%) 35 (1.5%)
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%)
Data are n (%) in patients treated with ≥1 dose of study drug
Exposure
32
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
HbA1c
6.0
6.5
7.0
7.5
8.0
8.5
9.0
Week
Ad
just
ed
me
an
(S
E)
Hb
A1
c (%
)
Placebo
Empagliflozin 10 mgEmpagliflozin 25 mg
2294
2296
2296
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2272
2272
2280
2188
2218
2212
2133
2150
2152
2113
2155
2150
2063
2108
2115
2008
2072
2080
1967
2058
2044
1741
1805
1842
1456
1520
1540
1241
1297
1327
1109
1164
1190
962
1006
1043
705
749
795
420
488
498
151
170
195
12 28 52 94 10880 12266 1360 150 164 178 192 20640
33
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
Weight
80
82
84
86
88
90
Week
Ad
just
ed
me
an
(S
E)
we
igh
t (k
g)
2285
2290
2283
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
1915
1893
1891
2215
2238
2226
2138
2174
2178
1598
1673
1678
1239
1298
1335
425
483
489
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
34
28 52 1080 164 22012
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
Waist circumference
101
102
103
104
105
106
107
WeekAd
just
ed
me
an
(S
E)
wa
ist
circ
um
-fe
ren
ce (
cm)
2259
2272
2273
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
1869
1836
1857
2183
2219
2209
2110
2155
2157
1562
1644
1648
1220
1285
1329
418
475
486
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
28 52 1080 164 22012
35
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
Systolic blood pressure
36
125
127
129
131
133
135
137
139
141
143
145
Week
Ad
just
ed
me
an
(S
E)
syst
olic
b
loo
d p
ress
ure
(m
mH
g)
2322
2322
2323
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2235
2250
2247
2203
2235
2221
2161
2193
2197
2133
2174
2169
2073
2125
2129
2024
2095
2102
1974
2072
2066
1771
1853
1878
1492
1556
1571
1274
1327
1351
1126
1189
1212
981
1034
1070
735
790
842
450
518
528
171
199
216
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
16 28 52 94 10880 12266 1360 150 164 178 192 20640
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
Diastolic blood pressure
37
70
71
72
73
74
75
76
77
78
79
80
Week
Ad
just
ed
me
an
(S
E)
dia
sto
lic
blo
od
pre
ssu
re (
mm
Hg
)
2322
2322
2323
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2235
2250
2247
2203
2235
2221
2161
2193
2197
2133
2174
2169
2073
2125
2129
2024
2095
2102
1974
2072
2066
1771
1853
1878
1492
1556
1571
1274
1327
1351
1126
1189
1212
981
1034
1070
735
790
842
450
518
528
171
199
216
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
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
16 28 52 94 10880 12266 1360 150 164 178 192 20640
Heart rate (ECG)
38
65
66
67
68
69
70
71
72
73
74
75
Week
Ad
just
ed
me
an
(S
E)
he
art
ra
te (
bp
m)
2174
2205
2192
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2127
2137
2127
2032
2064
2066
1928
2006
2006
1796
1877
1907
1300
1366
1383
1002
1045
1086
552
597
633
PlaceboEmpagliflozin 10
mgEmpagliflozin 25
mg
28 52 10880 1360 164 192
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
Low-density lipoprotein cholesterol
80
82
84
86
88
90
92
94
96
98
100
Week
Ad
just
ed
me
an
(S
E)
LD
L c
ho
lest
ero
l (m
g/d
L)
2297
2294
2287
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2273
2269
2256
2179
2205
2188
2104
2143
2132
2006
2072
2060
1932
1998
2020
1419
1474
1503
1086
1133
1169
694
740
779
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
28 52 10880 1360 164 1924
39
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
High-density lipoprotein cholesterol
40
41
42
43
44
45
46
47
48
49
50
Week
Ad
just
ed
me
an
(S
E)
HD
L c
ho
lest
ero
l (m
g/d
L)
2297
2295
2289
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2273
2270
2259
2181
2209
2191
2104
2144
2135
2007
2074
2064
1932
2001
2022
1419
1475
1507
1087
1134
1170
694
741
779
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
40
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 52 10880 1360 164 1924
Cardiovascular outcomesSilvio E Inzucchi
Professor of Medicine, Yale University School of Medicine, New Haven, CT, USA
41
Disclosure
• Consultations and non-financial support – Boehringer Ingelheim, Merck, Janssen, Novo Nordisk,
Sanofi/Regeron, Intarcia, Lexicon, Poxel, Takeda, Eli Lilly
• CME funding to Yale University– Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbott, Merck and
Sanofi
42
43
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)
44
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
0.5 1.0
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/ analysedEmpagliflozin Placebo HR (95% CI) p-value
Intent-to-treat population
490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382
3-point MACE: sensitivity analyses
Favours empagliflozin Favours placebo
45
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.
Patients with event/ analysedEmpagliflozin Placebo HR (95% CI) p-value
3-point MACE 490/4687 282/2333 0.86(0.74, 0.99)*
0.0382
CV death
CV death, MI and stroke
46
Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI
CV death
47
HR 0.62(95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio
CV death
48
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
Patients with event/analysedEmpagliflozin 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
Non-fatal stroke
CV death, MI and stroke
49
Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI
Patients with event/analysedEmpagliflozin 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
CV death, MI and stroke
50
Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI
0.5
Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value
Intent-to-treat population
164/4687 69/2333 1.18 (0.89, 1.56) 0.2567
Fatal and non-fatal stroke
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)
On-treatment analysis*
141/4607 66/2308 1.04 (0.78, 1.40) 0.7849
0.5
Favoursempagliflozin
Favoursplacebo
Numerical difference largely driven by events occurring >30 days after treatment
stop Favoursempagliflozin
Favoursplacebo
Patients with event/analysedEmpagliflozin 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
3-point MACE and 4-point MACE
52
Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI
Patients with event/analysedEmpagliflozin 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
3-point MACE and 4-point MACE
53
Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI
3-point MACE: subgroup analysisEmpagliflozi
nPlacebo
All patients 4687 2333Age, years 0.01<65 2596 1297≥65 2091 1036
Sex 0.81Male 3336 1680Female 1351 653
Race 0.09White 3403 1678Asian 1006 511Black/African-American 237 120
HbA1c, % 0.01<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 48860 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) 54
HR (95% CI)
CV death: subgroup analysesHR (95% CI)
Favours empagliflozin Favours placebo
55
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)
Empagliflozin
Placebo
All patients 4687 2333Age, years 0.21<65 2596 1297≥65 2091 1036
Sex 0.32Male 3336 1680Female 1351 653
Race 0.43White 3403 1678Asian 1006 511Black/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 48860 to <90 2425 1238<60 1212 607
p-value for interaction
Heart failure
56
Hospitalisation for heart failure
57
HR 0.65(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
Hospitalisation for heart failure
58
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
All-cause mortality
59
All-cause mortality
60
HR 0.68(95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
All-cause mortality
61
HR 0.68(95% CI 0.57, 0.82)
p<0.0001
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)
p=0.0003
Kaplan-Meier estimate. HR, hazard ratio
0.25 2.50
Patients with event/analysedEmpagliflozin 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 57/2333 0.84(0.60, 1.16)
0.2852
All-cause mortality, CV death and non-CV death
62
Favours empagliflozin Favours placebo
Cox regression analysis. CV, cardiovascular; HR, hazard ratio
Safety and tolerability David Fitchett, MD
Cardiologist, St Michael’s HospitalAssociate Professor of Medicine, University of
Toronto, Toronto, Canada
63
Disclosures
• Consultations– Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Sanofi, Merck
64
Adverse events
Rate = per100 patient-years
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
65
*As reported by the investigatorPatients treated with ≥1 dose of study drug
Adverse events consistent with urinary tract infection
Rate = per100 patient-years
Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
n (%) Rate n (%) Rate 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
66
Patients treated with ≥1 dose of study drug Based on 79 MedDRA preferred terms
Complicated urinary tract infectionPlacebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
n (%) Rate n (%) Rate 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 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
Rate = per100 patient-years
67
Patients treated with ≥1 dose of study drugEvents 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
Adverse events consistent with genital infection
Rate = per100 patient-years
Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
n (%) Rate n (%) Rate 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
68
Patients treated with ≥1 dose of study drug Based on 88 MedDRA preferred terms
Confirmed hypoglycaemic adverse eventsPlacebo (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%)
Events requiring assistance
28 (2.5%) 27 (2.4%) 25 (2.2%)
69
Patients treated with ≥1 dose of study drug Plasma glucose <3.9 mmol/L (70 mg/dL) and/or requiring assistance
Other adverse events (1)Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
n (%) Rate n (%) Rate n (%) Rate
Diabetic ketoacidosis* 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
Venous thrombotic events**
20(0.9%)
0.35 9(0.4%)
0.15 21(0.9%)
0.35Rate = per100 patient-years
70
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
Other adverse events (2)
71
Patients treated with ≥1 dose of study drug*Based on standardised MedDRA queries†Based on 62 MedDRA preferred terms
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
Electrolytes
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)
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)
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)
Changes in clinical laboratory parameters
72
Data are mean (SD) in patients treated with ≥1 dose of study drugChanges from baseline are at last value on treatment, defined as the last measurement ≤3 days after thelast intake of study drug
Implications for practice and conclusions
Bernard Zinman CM, MD, FRCP, FACPDirector, Leadership Sinai Centre for Diabetes
Professor of Medicine, University of Toronto
73
74
EMPA-REG OUTCOME®: Summary
• Empagliflozin reduced risk for 3-point MACE by 14%
• Empagliflozin was associated with a reduction in HbA1c without an increase in hypoglycaemia, reductions in weight and blood pressure, and small increases in LDL cholesterol and HDL cholesterol
• Empagliflozin was associated with an increase in genital infections but was otherwise well tolerated
MACE, Major Adverse Cardiovascular Event; HDL, high density lipoprotein; LDL, low density lipoprotein
75
EMPA-REG OUTCOME®: Summary
• Empagliflozin reduced hospitalisation for heart failure by 35%
• Empagliflozin reduced CV death by 38%
• Empagliflozin improved survival by reducing all-cause mortality by 32%
CV, cardiovascular
EMPA-REG OUTCOME®: Important features
• Population studied– A high CV risk population with modest hyperglycaemia on
standard glucose-lowering and CV therapy
• Follow-up and retention– 97.0% of patients completed the study and vital status was
available for 99.2% of patients
• Two doses of empagliflozin (10 mg and 25 mg) studied– Similar magnitude of reduction with both doses for CV
death, all-cause mortality and hospitalisation for heart failure
76
CV, cardiovascular
Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk
77
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
Simvastatin1
for 5.4 years
30High CV risk 5% diabetes, 26%
hypertension
1994 2000 2015
Pre-statin era
56 High CV risk
38% diabetes, 46% hypertension
Ramipril2for 5 years
Pre-ACEi/ARB era
<29% statin
Empagliflozin for 3 years
39T2DM with high CV risk
92% hypertension
>80% ACEi/ARB
>75% statin
EMPA-REG OUTCOME®:Therapeutic considerations
• Empagliflozin, as used in this trial, for 3 years in 1,000 patients with type 2 diabetes at high CV risk:
– 25 lives saved (82 vs 57 deaths)• 22 fewer CV deaths (59 vs 37)
– 14 fewer hospitalisations for heart failure (42 vs 28)
– 53 additional genital infections (22 vs 75)
78
79
EMPA-REG OUTCOME®: What effect will these results have on clinical practice guidelines?
Acknowledgements
• We are indebted to the study participants for their commitment to following the trial protocol including adherence to study medication, clinic visits and assessments
• We thank the physician investigators, coordinators and their staff from 590 sites in 42 countries who conscientiously enrolled participants and maintained excellent follow-up throughout the study
80
Acknowledgements
EMPA-REG OUTCOME® Steering Committee
Bernard Zinman [Chair], Lunenfeld-Tanenbaum Research Institute,
Toronto, Canada
Christoph Wanner, Würzburg University Clinic, Würzburg, Germany
John M. Lachin, The George Washington University, Rockville, MD, USA
David Fitchett, University of Toronto, Toronto, Canada
Erich Bluhmki, Boehringer Ingelheim, Biberach, Germany
Odd Erik Johansen, Boehringer Ingelheim KS, Asker, Norway
Hans J. Woerle, Boehringer Ingelheim, Ingelheim, Germany
Uli C. Broedl, Boehringer Ingelheim, Ingelheim, Germany
Silvio E. Inzucchi, Yale University School of Medicine, CT, USA
81
Acknowledgements
Data Safety Monitoring Board
Francine K. Welty, Beth Israel Deaconess Medical Center, Boston, USA
Klaus G. Parhofer, University of Munich, Munich, Germany
Terje R. Pedersen, Oslo University Hospital, Oslo, Norway
Kennedy R. Lees, University of Glasgow, Glasgow, UK
Tim Clayton, London School of Hygiene and Tropical Medicine, UK
Stuart Pocock, London School of Hygiene and Tropical Medicine, UK
Mike Palmer, N Zero 1 Ltd, Wilmslow, UK
82
Further reading
• The slides from this presentation are available at:www.empa-reg-outcome.com www.easd.org
• www.nejm.org
83