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 ra

tio (9

5% C

I) (d

iabe

tes v

s no

diab

etes

)

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;364:829-414

.

0

76543210

40 50 60 70 80 90Age (years)

Year

s of l

ife lo

st

Men76543210

40 50 60 70 80 900Age (years)

WomenNon-vascular deathsVascular 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 eventsMore

intensiveLess

intensiveDifference 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)

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 eventsMore

intensiveLess

intensiveDifference 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)

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

81. 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;12:90-100 9

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

10CV, cardiovascular

Trial designJohn 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

North America, Australia, New ZealandLatin America

Asia

AfricaEurope

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 event14

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 dispositionPlacebo Empagliflozin

10 mgEmpagliflozi

n 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

18CV, 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

20HDL, 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 MACE2. Test of non-inferiority for 4-point MACE3. 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

21MACE; 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

Adju

sted

mea

n (S

E) H

bA1c

(%)

PlaceboEmpagliflozin 10

mgEmpagliflozin 25 mg

229422962296

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

227222722280

218822182212

213321502152

211321552150

206321082115

200820722080

196720582044

174118051842

145615201540

124112971327

110911641190

96210061043

705749795

420488498

151170195

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

Adju

sted

mea

n (S

E) w

eigh

t (kg

)

228522902283

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

191518931891

221522382226

213821742178

159816731678

123912981335

425483489

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

WeekAdju

sted

mea

n (S

E) w

aist

circ

um-

fere

nce

(cm

)

225922722273

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

186918361857

218322192209

211021552157

156216441648

122012851329

418475486

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

125127129131133135137139141143145

Week

Adju

sted

mea

n (S

E) s

ysto

lic

bloo

d pr

essu

re (m

mHg

)

232223222323

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

223522502247

220322352221

216121932197

213321742169

207321252129

202420952102

197420722066

177118531878

149215561571

127413271351

112611891212

98110341070

735790842

450518528

171199216

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

7071727374757677787980

Week

Adju

sted

mea

n (S

E) d

iast

olic

bloo

d pr

essu

re (m

mHg

)

232223222323

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

223522502247

220322352221

216121932197

213321742169

207321252129

202420952102

197420722066

177118531878

149215561571

127413271351

112611891212

98110341070

735790842

450518528

171199216

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

6566676869707172737475

Week

Adju

sted

mea

n (S

E)

hear

t rat

e (b

pm)

217422052192

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

212721372127

203220642066

192820062006

179618771907

130013661383

100210451086

552597633

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

80828486889092949698

100

Week

Adju

sted

mea

n (S

E)

LDL

chol

este

rol (

mg/

dL)

229722942287

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

227322692256

217922052188

210421432132

200620722060

193219982020

141914741503

108611331169

694740779

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

4041424344454647484950

Week

Adju

sted

mea

n (S

E)

HDL

chol

este

rol (

mg/

dL)

229722952289

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

227322702259

218122092191

210421442135

200720742064

193220012022

141914751507

108711341170

694741779

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 MACEEmpagliflozin 10

mgHR 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 placeboCox 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 placeboCox 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 placeboCox 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 population164/4687 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 placeboCox 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 placeboCox 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 placeboFor 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 (%) RateOne 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 (%) RateEvents 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 sexMale 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 (%) RateEvents 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 sexMale 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 (%) RateHepatic 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

baselineHaematocrit, % 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

76CV, 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 CommitteeBernard Zinman [Chair], Lunenfeld-Tanenbaum Research Institute, Toronto, CanadaChristoph Wanner, Würzburg University Clinic, Würzburg, GermanyJohn M. Lachin, The George Washington University, Rockville, MD, USADavid Fitchett, University of Toronto, Toronto, CanadaErich Bluhmki, Boehringer Ingelheim, Biberach, GermanyOdd Erik Johansen, Boehringer Ingelheim KS, Asker, NorwayHans 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 BoardFrancine K. Welty, Beth Israel Deaconess Medical Center, Boston, USA Klaus G. Parhofer, University of Munich, Munich, GermanyTerje R. Pedersen, Oslo University Hospital, Oslo, NorwayKennedy R. Lees, University of Glasgow, Glasgow, UKTim Clayton, London School of Hygiene and Tropical Medicine, UKStuart Pocock, London School of Hygiene and Tropical Medicine, UKMike 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