Introduction
Bernard Zinman CM, MD, FRCP, FACP
Director, Leadership Sinai Centre for Diabetes
Professor 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
Type 2 diabetes is increasingly prevalent
• Globally, 387 million people • At least 68% of people >65 years
are living with diabetes1
with diabetes die of heart disease2
Hazard ratio (95% CI)
(diabetes vs no diabetes)
Mortality risk associated with
diabetes (n=820,900)3
3
This will rise to 592
million by 20351
2
1
0
CV death
All-cause
mortality
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
3
Diabetes is associated with significant loss of
life years
Men
7
Non-vascular deaths
Years of life lost
6
Vascular deaths
6
5
4
4
3
3
2
2
1
1
0 40
50
60
70
Age (years)
.
7
5
0
80
90
Women
0
0 40
50
60
70
80
90
Age (years)
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
Seshasai et al. N Engl J Med 2011;364:829-41
4
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
5
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
6
Recent trials of newer glucose-lowering agents
have been neutral on the primary CV outcome
HR: 1.0
(95% CI: 0.89, 1.12)
SAVOR-TIMI 53
HR: 0.96
(95% CI: UL ≤1.16)
EXAMINE
2013
HR: 0.98
(95% CI: 0.88, 1.09)
TECOS
2014
HR: 1.02
(95% CI: 0.89, 1.17)
2015
ELIXA
DPP-4 inhibitors*
Lixisenatide
EMPA-REG OUTCOME®
Empagliflozin
CV, cardiovascular; HR, hazard ratio; DPP-4, dipeptidyl peptidase-4
*Saxagliptin, alogliptin, sitagliptin
Adapted from Johansen OE. World J Diabetes 2015;6:1092-96
7
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
1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93
8
Empagliflozin modulates several factors related
to CV risk
Other
BP
Arterial stiffness
Albuminuria
Sympathetic
nervous system
activity
Uric acid
Glucose
Insulin
↑LDL-C
↑HDL-C
Triglycerides
Weight
Visceral adiposity
Oxidative stress
Adapted from Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100
9
EMPA-REG OUTCOME®
• Randomised, double-blind, placebo-controlled CV
outcomes trial
• Objective
To 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
CV, cardiovascular
10
Trial design
John M Lachin, ScD
Professor 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
590 sites in 42 countries
Asia
North America, Australia, New Zealand
Latin America
Europe
Africa
13
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
14
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)
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
17
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
18
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
CV, cardiovascular; MI, myocardial infarction
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
HDL, high density lipoprotein; LDL, low density lipoprotein
20
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
MACE; Major Adverse Cardiovascular Event; NDA, New Drug Application; FDA, Food and Drug Administration
21
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, MD
Professor 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)
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
26
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
27
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
28
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”
29
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
30
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
31
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
32
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
33
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
34
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
35
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
36
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
37
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
38
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
39
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
40
Cardiovascular outcomes
Silvio 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
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)
43
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
44
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.
45
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
46
CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio
47
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
48
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)*
CV death
172/4687
0.0382
137/2333 0.62 (0.49, 0.77)
<0.0001
Non-fatal MI
Non-fatal stroke
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
49
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
50
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
52
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
53
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
2.00
4.00
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
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
2.00
4.00
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)
55
Heart failure
56
Hospitalisation for heart failure
HR 0.65
(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
57
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
58
All-cause mortality
59
All-cause mortality
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
60
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
61
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
62
Safety and tolerability
David Fitchett, MD
Cardiologist, St Michael’s Hospital
Associate Professor of Medicine, University of Toronto,
Toronto, Canada
63
Disclosures
• Consultations
– Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Sanofi, Merck
64
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
65
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
66
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
67
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
68
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
69
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
70
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
71
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
72
Implications for practice
and conclusions
Bernard Zinman CM, MD, FRCP, FACP
Director, Leadership Sinai Centre for Diabetes
Professor of Medicine, University of Toronto
73
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
74
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
75
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
CV, cardiovascular
76
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
77
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
EMPA-REG OUTCOME®: What effect will these
results have on clinical practice guidelines?
79
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