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 are living with diabetes 1 3 At least 68% of people >65 years with diabetes die of heart disease 2 This will rise to 592 million by IDF Diabetes Atlas 6th Edition Centers for Disease Control and Prevention 2011; 3. Seshasai et al. N Engl J Med 2011;364:829-41http:// 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: Age (years) Years of life lost Men 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

Number of events More intensive Less intensive Difference in HbA1c (%) HR (95% CI) Stroke (0.83, 1.10) Myocardial infarction (0.76, 0.94) Hospitalisation for or death from heart failure (0.86, 1.16) Meta-analysis of intensive glucose control in T2DM: major CV events including heart failure 5 Favours more intensiveFavours 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

Number of events More intensive Less intensive Difference in HbA1c (%) HR (95% CI) All-cause mortality (0.90,1.20) CV death (0.84,1.42) Non-CV death (0.89,1.18) Meta-analysis of intensive glucose control in T2DM: mortality 6 Favours more intensiveFavours 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

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) TECOS HR: 0.98 (95% CI: 0.88, 1.09) EMPA-REG OUTCOME ® ELIXA HR: 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, sitagliptin Adapted from Johansen OE. World J Diabetes 2015;6:

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 to 1 : – 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:  BP  Arterial stiffness  BP  Arterial stiffness  Glucose  Insulin  Glucose  Insulin  Albuminuria  Uric acid Other ↑LDL-C ↑HDL-C  Triglycerides ↑LDL-C ↑HDL-C  Triglycerides  Oxidative stress  Sympathetic nervous system activity  Weight  Visceral adiposity

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 10 CV, cardiovascular

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 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 15 th 2010: First patient entered April 13 th 2013: Last patient entered December 15 th 2014: Closeout (final visits) started April 13 th 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 PlaceboEmpagliflozin 10 mg Empagliflozin 25 mg N (%) Intent-to-treat population2333 (100)2345 (100)2342 (100) Discontinued study drug prematurely 683 (29.3)555 (23.7)542 (23.1) Completed study or died2266 (97.1)2264 (96.5) Vital status available2316 (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/m 2 –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/1.73m 2 (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

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 CV, cardiovascular; MI, myocardial infarction

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 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≤ 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, 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) Age, years63.2 (8.8)63.0 (8.6)63.2 (8.6) Male1680 (72.0)1653 (70.5)1683 (71.9) Region Europe959 (41.1)966 (41.2)960 (41.0) North America*462 (19.8)466 (19.9) Asia450 (19.3)447 (19.1)450 (19.2) Latin America360 (15.4)359 (15.3)362 (15.5) Africa102 (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) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) HbA1c, %8.08 (0.84)8.07 (0.86)8.06 (0.84) Time since diagnosis of type 2 diabetes, years ≤5≤5423 (18.1)406 (17.3)434 (18.6) >5 to (24.5)585 (24.9)590 (25.2) > (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, mmHg135.8 (17.2)134.9 (16.8)135.6 (17.0) Diastolic blood pressure, mmHg76.8 (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/dL84.9 (35.3)86.3 (36.7)85.5 (35.2) HDL cholesterol, mg/dL44.0 (11.3)44.7 (12.0)44.5 (11.8) eGFR, mL/min/1.73m 2 (MDRD)73.8 (21.1)74.3 (21.8)74.0 (21.4) ≥90 mL/min/1.73m (20.9%)519 (22.1%)531 (22.7%) 60 to <90 mL/min/1.73m (53.1%)1221 (52.1%)1204 (51.4%) <60 mL/min/1.73m (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/m (5.2)30.6 (5.2)30.6 (5.3) Weight, kg86.6 (19.1)85.9 (18.8)86.5 (19.0) Waist circumference, cm105.0 (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 complications Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Any CV risk factor2307 (98.9%)2333 (99.5%)2324 (99.2%) Coronary artery disease1763 (75.6%)1782 (76.0%)1763 (75.3%) Multi-vessel coronary artery disease 1100 (47.1%)1078 (46.0%)1101 (47.0%) History of MI1083 (46.4%)1107 (47.2%)1083 (46.2%) Coronary artery bypass graft563 (24.1%)594 (25.3%)581 (24.8%) History of stroke553 (23.7%)535 (22.8%)549 (23.4%) Peripheral artery disease479 (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”

Baseline characteristics: CV medication (1) 30 Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Anti-hypertensive therapy2221 (95.2%)2227 (95.0%)2219 (94.7%) ACE inhibitors/ARBs1868 (80.1%)1896 (80.9%)1902 (81.2%) Beta-blockers1498 (64.2%)1530 (65.2%)1526 (65.2%) Diuretics988 (42.3%)1036 (44.2%)1011 (43.2%) Calcium channel blockers788 (33.8%)781 (33.3%)748 (31.9%) Mineralocorticoid receptor antagonists 136 (5.8%)157 (6.7%)148 (6.3%) Renin inhibitors19 (0.8%)16 (0.7%)11 (0.5%) Other191 (8.2%)193 (8.2%)190 (8.1%) Data are n (%) in patients treated with ≥1 dose of study drug ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers

Baseline characteristics: CV medication (2) 31 Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Lipid-lowering drugs1864 (79.9%)1926 (82.1%)1894 (80.9%) Statins1773 (76.0%)1827 (77.9%)1803 (77.0%) Fibrates199 (8.5%)214 (9.1%)217 (9.3%) Ezetimibe81 (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, years2.6 ( )2.6 ( )2.6 ( ) Observation time, years3.1 ( )3.2 ( ) Data are median (interquartile range) in patients treated with ≥1 dose of study drug

HbA1c 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

Weight Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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

Waist circumference Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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

Systolic blood pressure Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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

Diastolic blood pressure Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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

Heart rate (ECG) Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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

Low-density lipoprotein cholesterol Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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

High-density lipoprotein cholesterol Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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

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 43 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 ≤ )

3-point MACE 44 Empagliflozin 10 mg HR 0.85 (95% CI 0.72, 1.01) p= Empagliflozin 25 mg HR 0.86 (95% CI 0.73, 1.02) p= Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio

On-treatment analysis** 407/ / (0.74, 1.02) Per protocol analysis*** 487/ / (0.75, 1.00) Patients with event/ analysed EmpagliflozinPlaceboHR(95% CI) p -value Intent-to-treat population 490/ / (0.74, 0.99)* point MACE: sensitivity analyses Favours empagliflozinFavours 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/ analysed EmpagliflozinPlaceboHR(95% CI) p -value 3-point MACE490/ / (0.74, 0.99)* 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< Cumulative incidence function. HR, hazard ratio

CV death 48 Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p= Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77) p= Cumulative incidence function. HR, hazard ratio

Patients with event/analysed EmpagliflozinPlaceboHR(95% CI) p -value 3-point MACE490/ / (0.74, 0.99)* CV death172/ / (0.49, 0.77)< 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/analysed EmpagliflozinPlaceboHR(95% CI) p -value 3-point MACE490/ / (0.74, 0.99)* CV death172/ / (0.49, 0.77)< Non-fatal MI213/ / (0.70, 1.09) Non-fatal stroke150/468760/ (0.92, 1.67) 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

Patients with event/analysed EmpagliflozinPlaceboHR(95% CI) p -value Intent-to-treat population 164/468769/ (0.89, 1.56) 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* 141/460766/ (0.78, 1.40) Favours empagliflozin Favours placebo Numerical difference largely driven by events occurring >30 days after treatment stop Favours empagliflozin Favours placebo

Patients with event/analysed EmpagliflozinPlaceboHR(95% CI) p -value 3-point MACE490/ / (0.74, 0.99)* CV death172/ / (0.49, 0.77)< Non-fatal MI213/ / (0.70, 1.09) Non-fatal stroke150/468760/ (0.92, 1.67) 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/analysed EmpagliflozinPlaceboHR(95% CI) p -value 3-point MACE490/ / (0.74, 0.99)* CV death172/ / (0.49, 0.77)< Non-fatal MI213/ / (0.70, 1.09) Non-fatal stroke150/468760/ (0.92, 1.67) point MACE599/ / (0.78, 1.01)* 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 analysis EmpagliflozinPlacebo All patients Age, years0.01 < ≥ Sex0.81 Male Female Race0.09 White Asian Black/African-American HbA1c, %0.01 < ≥ Body mass index, kg/m < ≥ eGFR, mL/min/1.73m ≥ to < < p-value for interaction Favours empagliflozinFavours 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 analyses HR (95% CI) Favours empagliflozinFavours 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) EmpagliflozinPlacebo All patients Age, years0.21 < ≥ Sex0.32 Male Female Race0.43 White Asian Black/African-American HbA1c, %0.51 < ≥ Body mass index, kg/m < ≥ eGFR, mL/min/1.73m ≥ to < < p-value for interaction

Heart failure 56

Hospitalisation for heart failure 57 HR 0.65 (95% CI 0.50, 0.85) p= Cumulative incidence function. HR, hazard ratio

Hospitalisation for heart failure 58 Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86) p= Empagliflozin 25 mg HR 0.68 (95% CI 0.50, 0.93) p= Cumulative incidence function. HR, hazard ratio

All-cause mortality 59

All-cause mortality 60 HR 0.68 (95% CI 0.57, 0.82) p< Kaplan-Meier estimate. HR, hazard ratio

All-cause mortality 61 HR 0.68 (95% CI 0.57, 0.82) p< Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) p= Empagliflozin 25 mg HR 0.67 (95% CI 0.54, 0.83) p= Kaplan-Meier estimate. HR, hazard ratio

Patients with event/analysed EmpagliflozinPlaceboHR95% CI p -value All-cause mortality269/ / (0.57, 0.82)< CV death172/ / (0.49, 0.77)< Non-CV death97/468757/ (0.60, 1.16) 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 Hospital Associate 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 (%)Raten (%)Raten (%)Rate One or more AEs2139 (91.7%) (90.1%) (90.4%) One or more drug-related* AEs 549 (23.5%) (28.4%) (27.5%) One or more AEs leading to discontinuation 453 (19.4%) (17.7%) (17.0%) 6.89 One or more serious AEs988 (42.3%) (37.4%) (39.0%) *As reported by the investigator Patients 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 (%)Raten (%)Raten (%)Rate Events consistent with UTI423 (18.1%) (18.2%) (17.8%) 7.75 Events leading to discontinuation 10 (0.4%) (0.9%) (0.8%) 0.31 By sex Male158 (9.4%) (10.9%) (10.1%) 4.09 Female265 (40.6%) (35.5%) (37.3%) Patients treated with ≥1 dose of study drug Based on 79 MedDRA preferred terms

Complicated urinary tract infection Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%)Raten (%)Raten (%)Rate Complicated urinary tract infection* 41 (1.8%) (1.4%) (2.0%) 0.80 Urinary tract infection 16 (0.7%) (0.6%) (0.7%) 0.27 Pyelonephritis † 22 (0.9%) (0.6%) (0.9%) 0.33 Urosepsis 3 (0.1%) (0.3%) (0.5%) 0.18 Rate = per100 patient-years 67 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

Adverse events consistent with genital infection Rate = per100 patient-years Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%)Raten (%)Raten (%)Rate Events consistent with genital infection 42 (1.8%) (6.5%) (6.3%) 2.55 Serious events3 (0.1%) (0.2%) (0.2%) 0.07 Events leading to discontinuation 2 (0.1%) (0.8%) (0.6%) 0.23 By sex Male25 (1.5%) (5.4%) (4.6%) 1.78 Female17 (2.6%) (9.2%) (10.8%) Patients treated with ≥1 dose of study drug Based on 88 MedDRA preferred terms

Confirmed hypoglycaemic adverse events Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Confirmed hypoglycaemic adverse events 650 (27.9%)656 (28.0%)647 (27.6%) Events requiring assistance 36 (1.5%)33 (1.4%)30 (1.3%) Patients taking insulin at baseline Total483 (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 (%)Raten (%)Raten (%)Rate Diabetic ketoacidosis*1 (<0.1%) (0.1%) (<0.1%) 0.02 Acute kidney injury † 155 (6.6%) (5.2%) (5.3%) 2.12 Events consistent with volume depletion § 115 (4.9%) (4.9%) (5.3%) 2.11 Serious events24 (1.0%) (0.8%) (1.1%) 0.43 Events leading to discontinuation 7 (0.3%) (<0.1%) (0.2%) 0.07 Venous thrombotic events**20 (0.9%) (0.4%) (0.9%) 0.35 Rate = 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 (%)Raten (%)Raten (%)Rate Hepatic injury*108 (4.6%) (3.4%) (3.8%) 1.48 Hypersensitivity*197 (8.4%) (6.7%) (7.7%) 3.14 Bone fractures † 91 (3.9%) (3.9%) (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/1.73m (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 drug Changes from baseline are at last value on treatment, defined as the last measurement ≤3 days after the last intake of study drug

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 74 MACE, Major Adverse Cardiovascular Event; HDL, high density lipoprotein; LDL, low density lipoprotein

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% 75 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 S investigator. Lancet 1994; 344: , 2. HOPE investigator N Engl J Med 2000;342:145-53, Simvastatin 1 for 5.4 years High CV risk 5% diabetes, 26% hypertension Pre-statin era High CV risk 38% diabetes, 46% hypertension Ramipril 2 for 5 years Pre-ACEi/ARB era <29% statin Empagliflozin for 3 years T2DM 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

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: