Safety and tolerability David Fitchett, MD Cardiologist, St Michael’s Hospital Associate Professor of Medicine, University of Toronto, Toronto, Canada

Disclosures Consultations Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Sanofi, Merck

Adverse events Placebo (n=2333) Empagliflozin 10 mg (n=2345) 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 tlr-1245_0025final—01-1501. Table 15.1.4.1: 1 Demographic data − treated set. Rate = per100 patient-years *As reported by the investigator Patients treated with ≥1 dose of study drug

Adverse events consistent with urinary tract infection Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate Events consistent with UTI 423 (18.1%) 8.21 426 (18.2%) 8.02 416 (17.8%) 7.75 Events leading to discontinuation 10 (0.4%) 0.17 22 (0.9%) 0.37 19 (0.8%) 0.31 By sex Male 158 (9.4%) 3.96 180 (10.9%) 4.49 170 (10.1%) 4.09 Female 265 (40.6%) 22.81 246 (35.5%) 18.83 246 (37.3%) 20.38 Total: Table 15.3.1.6: 1 Rate = per100 patient-years 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 (%) 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 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 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 Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate Events consistent with genital infection 42 (1.8%) 0.73 153 (6.5%) 2.66 148 (6.3%) 2.55 Serious events 3 (0.1%) 0.05 5 (0.2%) 0.08 4 (0.2%) 0.07 Events leading to discontinuation 2 (0.1%) 0.03 19 (0.8%) 0.32 14 (0.6%) 0.23 By sex Male 25 (1.5%) 0.60 89 (5.4%) 2.16 77 (4.6%) 1.78 Female 17 (2.6%) 1.09 64 (9.2%) 3.93 71 (10.8%) 4.81 Overall: table 15.3.1.8: 1 Serious: table 15.3.1.8: 4 Leading to discontinuation: table 15.3.1.8: 5 Rate = per100 patient-years 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 Total 483 (42.6%) 494 (43.6%) 464 (41.4%) 28 (2.5%) 27 (2.4%) 25 (2.2%) Overall n(%): table 15.3.1.4: 4 Requiring assistance n (%): table 15.3.1.4: 4 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 Diabetic ketoacidosis* 1 (<0.1%) 0.02 3 (0.1%) 0.05 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 1.97 124 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 4 (0.2%) 0.07 Venous thrombotic events** 20 (0.9%) 0.35 9 (0.4%) 0.15 21 Table 15.3.1.1: 1 (tir), n(%) 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

Other adverse events (2) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) 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 1.57 87 (3.7%) 1.46 Rate = per100 patient-years Table 15.3.1.1: 1 (tir), n(%) Patients treated with ≥1 dose of study drug *Based on standardised MedDRA queries †Based on 62 MedDRA preferred terms

Changes in clinical laboratory parameters Electrolytes  Sodium, mEq/L 141 (2) 0 (2) Potassium, mEq/L 4.3 (0.4) 0.0 (0.4) Calcium, mg/dL 9.7 (0.5) 0.0 (0.5) 9.7 (0.4) Magnesium, mEq/L 1.7 (0.2) 0.0 (0.2) 0.1 (0.2) Phosphate, mg/dL 3.7 (0.3) 0.0 (0.3) 0.1 (0.3) 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)   Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) 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) 0.8 (1.3) 13.5 (1.5) 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