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

Empagliflozin modulates several factors related to CV risk BP Arterial stiffness Other Albuminuria Uric acid Glucose Insulin Sympathetic nervous system activity ↑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

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

Trial design John M Lachin, ScD Professor of Biostatistics and Epidemiology, and Statistics, The George Washington University, Rockville, USA

Disclosure Consultations Boehringer Ingelheim, Merck and Co., Gilead, Janssen, Novartis, AstraZeneca

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

Randomised and treated Trial design Placebo (n=2333) Screening (n=11531) Randomised and treated (n=7020) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Study medication was given in addition to standard of care Glucose-lowering therapy was to remain unchanged for first 12 weeks Treatment assignment double masked The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event

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

Patient disposition Placebo Empagliflozin 10 mg Empagliflozin 25 mg 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) Vital status available 2316 (99.3) 2324 (99.1) 2327 (99.4) 6809 (97%) completed study or died 1780 (25%) discontinued study drug prematurely, more in placebo All but 214 (3%) completed study or died Vital status assessed in 99%

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

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

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

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

Statistical testing strategy for MACE Analysis compared empagliflozin 10 mg and 25 mg (pooled) versus placebo Hierarchy to be used: Test of non-inferiority for 3-point MACE Test of non-inferiority for 4-point MACE Test of superiority for 3-point MACE 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

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

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