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1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375: DOI: /NEJMoa

2 Supplement to: Wanner C, Inzucchi SE, Lachin J, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. Figure S1. Pre-specified subgroup analyses for incident or worsening nephropathy Figure S2. Incident or worsening nephropathy with empagliflozin 10 mg, empagliflozin 25 mg and placebo... 3 Figure S3. Incident or worsening nephropathy or cardiovascular death with empagliflozin and placebo... 4 Figure S4. Incident or worsening nephropathy with empagliflozin and placebo in patients with prevalent kidney disease defined as egfr (MDRD) <60 ml/min/1.73m 2 and/or macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline... 6 Figure S5. Composite of doubling of serum creatinine (accompanied by egfr [MDRD] 45 ml/min/1.73m 2 ), initiation of renal replacement therapy, or death due to renal disease in patients with macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline... 7 Figure S6. Post-hoc subgroup analyses of doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease Figure S7. egfr according to CKD-EPI formula over 192 weeks in patients with egfr <60 ml/min/1.73m 2 and 60 ml/min/1.73m 2 at baseline Figure S8. Adverse events with empagliflozin compared with placebo Figure S9. Acute renal failure and acute kidney injury with empagliflozin and placebo Table S1. Baseline characteristics of patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline Table S2. Cardiovascular medications introduced post-baseline in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline Table S3. Composite microvascular outcome with empagliflozin compared with placebo Table S4. Incident or worsening nephropathy and incident or worsening nephropathy or cardiovascular death: pre-specified analysis and post-hoc sensitivity analysis Table S5. Incident or worsening nephropathy and incident or worsening nephropathy or cardiovascular death with empagliflozin compared with placebo in patients with prevalent kidney disease defined as egfr (MDRD) <60 ml/min/1.73m 2 and/or macroalbuminuria (urine albuminto-creatinine ratio >300 mg/g) at baseline Table S6. Adverse events in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline Table S7. Complicated urinary tract infections by MedDRA preferred term in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline Table S8. Changes in clinical laboratory parameters in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline

p-value is for test of homogeneity of treatment group difference among subgroups (test for treatment group by

3 Figure S1. Pre-specified subgroup analyses for incident or worsening nephropathy. Cox regression analyses in patients treated with 1 dose of study drug. p-value is for test of homogeneity of treatment group difference among subgroups (test for treatment group by covariate interaction) with no adjustment for multiple testing. ACE, angiotensin-converting enzyme. ARB, angiotensin-receptor blocker. DBP, diastolic blood pressure. SBP, systolic blood pressure. 2

4 Figure S2. Incident or worsening nephropathy with empagliflozin 10 mg, empagliflozin 25 mg and placebo Kaplan-Meier estimates of time to first occurrence of incident or worsening nephropathy in the empagliflozin 10 mg, empagliflozin 25 mg and placebo groups in patients treated with 1 dose of study drug. Hazard ratio is based on Cox regression analysis. Pre-specified analyses. 3

5 Figure S3. Incident or worsening nephropathy or cardiovascular death with empagliflozin and placebo Kaplan-Meier estimates of time to first occurrence of incident or worsening nephropathy or cardiovascular death in the empagliflozin pooled and placebo groups (Panel A) and in the empagliflozin 10 mg, empagliflozin 25 mg and placebo groups (Panel B) in patients treated with 1 dose of study drug. Hazard ratios are based on Cox regression analyses. Pre-specified analyses. A Empagliflozin pooled and placebo groups 4

6 B Empagliflozin 10 mg, empagliflozin 25 mg and placebo groups 5

7 Figure S4. Incident or worsening nephropathy with empagliflozin and placebo in patients with prevalent kidney disease defined as egfr (MDRD) <60 ml/min/1.73m 2 and/or macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline Kaplan-Meier estimates of time to first occurrence of incident or worsening nephropathy in the empagliflozin and placebo groups in patients with prevalent kidney disease treated with 1 dose of study drug. Hazard ratio is based on Cox regression analysis. Post-hoc analyses. egfr, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease. 6

8 Figure S5. Composite of doubling of serum creatinine (accompanied by egfr [MDRD] 45 ml/min/1.73m 2 ), initiation of renal replacement therapy, or death due to renal disease in patients with macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline Kaplan-Meier estimates in empagliflozin and placebo groups in patients with macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline treated with 1 dose of study drug. Hazard ratio is based on Cox regression analysis. Post-hoc analyses. egfr, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease. 7

9 Figure S6. Post-hoc subgroup analyses of doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease. Cox regression analyses in patients treated with 1 dose of study drug. p-value is for test of homogeneity of treatment group difference among subgroups (test for treatment group by covariate interaction) with no adjustment for multiple testing. 8

10 Figure S7. egfr according to CKD-EPI formula over 192 weeks in patients with egfr <60 ml/min/1.73m 2 and 60 ml/min/1.73m 2 at baseline. egfr according to CKD-EPI formula over 192 weeks in patients with egfr <60 ml/min/1.73m2 at baseline (Panel A) and 60 ml/min/1.73m2 at baseline (Panel B). egfr category at baseline is according to the MDRD formula. Post-hoc analysis. Mixed model repeated measures analysis, including baseline glycated hemoglobin as a linear covariate and region, baseline egfr (MDRD), baseline body mass index, the last week a patient could have had egfr measurements, treatment, visit, visit by treatment interaction, baseline glycated hemoglobin by visit interaction, baseline egfr by visit interaction, baseline egfr by treatment interaction and baseline egfr by visit by treatment interaction as fixed effects, in patients treated with 1 dose of study drug. egfr, estimated glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; MDRD, Modification of Diet in Renal Disease. A Patients with egfr <60 ml/min/1.73m 2 at baseline 9

11 B Patients with egfr 60 ml/min/1.73m 2 at baseline 10

with placebo based on post-hoc assessments.

12 Figure S8. Adverse events with empagliflozin compared with placebo. Incidence rate ratios (based on rate per 100 patient-years) for empagliflozin compared with placebo based on post-hoc assessments. Data are from patients treated with 1 dose of study drug based on events that occurred during treatment or 7 days after the last intake of study drug. 11

13 * Plasma glucose 70 mg/dl and/or requiring assistance. Based on 79 MedDRA preferred terms. Pyelonephritis, urosepsis or serious adverse event consistent with urinary tract infection. Based on 88 MedDRA preferred terms. Based on 8 MedDRA preferred terms. ǁ Based on the narrow standardized MedDRA query acute renal failure. ** Based on 1 standardized MedDRA query. Based on 62 MedDRA preferred terms. Based on 2 MedDRA preferred terms. egfr, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease. MedDRA, Medical Dictionary for Regulatory Activities. 12

14 Figure S9. Acute renal failure and acute kidney injury with empagliflozin and placebo. Kaplan-Meier estimates of time to first occurrence of acute renal failure based on the narrow standardized MedDRA query acute renal failure and time to first occurrence of acute kidney injury (MedDRA preferred term) in the empagliflozin and placebo groups in patients treated with 1 dose of study drug based on events that occurred during treatment or 7 days after the last intake of study drug. Post-hoc analyses. MedDRA, Medical Dictionary for Regulatory Activities. 13

15 Table S1. Baseline characteristics of patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline Patients with egfr (MDRD) <60 ml/min/1.73m 2 at baseline Patients with egfr (MDRD) 60 ml/min/1.73m 2 at baseline Characteristic* Placebo (N=607) Empagliflozin (N=1212) Placebo (N=1726) Empagliflozin (N=3473) Age years 67.1± ± ± ±8.5 Male no. (%) 418 (68.9) 816 (67.3) 1262 (73.1) 2518 (72.5) Race no. (%) White 444 (73.1) 878 (72.4) 1234 (71.5) 2524 (72.7) Asian 132 (21.7) 265 (21.9) 379 (22.0) 741 (21.3) Black/African-American 27 (4.4) 56 (4.6) 93 (5.4) 181 (5.2) Other/Missing 4 (0.7) 13 (1.1) 20 (1.2) 27 (0.8) Ethnicity no. (%) Not Hispanic or Latino 507 (83.5) 1000 (82.5) 1405 (81.4) 2835 (81.6) Hispanic or Latino 99 (16.3) 211 (17.4) 319 (18.5) 634 (18.3) Missing 1 (0.2) 1 (0.1) 2 (0.1) 4 (0.1) Region no. (%) Europe 210 (34.6) 418 (34.5) 749 (43.4) 1508 (43.4) North America (plus Australia and 175 (28.8) 329 (27.1) 287 (16.6) 603 (17.4) New Zealand) Asia 113 (18.6) 232 (19.1) 337 (19.5) 665 (19.1) Latin America 79 (13.0) 174 (14.4) 281 (16.3) 545 (15.7) Africa 30 (4.9) 59 (4.9) 72 (4.2) 152 (4.4) Weight kg 87.1± ± ± ±18.7 Body mass index kg/m ± ± ± ±5.2 CV risk factor no. (%) 601 (99.0) 1203 (99.3) 1706 (98.8) 3452 (99.4) Coronary artery disease 482 (79.4) 938 (77.4) 1281 (74.2) 2606 (75.0) Multi-vessel coronary artery 331 (54.5) 610 (50.3) 769 (44.6) 1569 (45.2) disease History of myocardial infarction 264 (43.5) 559 (46.1) 819 (47.5) 1630 (46.9) Coronary artery bypass graft 196 (32.3) 380 (31.4) 367 (21.3) 795 (22.9) History of stroke 156 (25.7) 293 (24.2) 397 (23.0) 791 (22.8) Peripheral artery disease 130 (21.4) 314 (25.9) 349 (20.2) 667 (19.2) Single vessel coronary artery 54 (8.9) 108 (8.9) 184 (10.7) 390 (11.2) 14

16 disease Cardiac failure 89 (14.7) 174 (14.4) 155 (9.0) 288 (8.3) Glycated hemoglobin ǁ % 8.03± ± ± ±0.84 Time since diagnosis of type 2 diabetes no. (%) 1 years 9 (1.5) 23 (1.9) 43 (2.5) 105 (3.0) >1 to 5 years 55 (9.1) 121 (10.0) 316 (18.3) 591 (17.0) >5 to 10 years 121 (19.9) 274 (22.6) 450 (26.1) 901 (25.9) >10 years 422 (69.5) 794 (65.5) 917 (53.1) 1876 (54.0) Glucose-lowering therapy no. (%) Medication taken alone or in combination Metformin 369 (60.8) 711 (58.7) 1365 (79.1) 2746 (79.1) Sulfonylurea 234 (38.6) 480 (39.6) 758 (43.9) 1534 (44.2) Thiazolidinedione 27 (4.4) 62 (5.1) 74 (4.3) 136 (3.9) Insulin 357 (58.8) 699 (57.7) 778 (45.1) 1551 (44.7) Monotherapy 217 (35.7) 430 (35.5) 474 (27.5) 950 (27.4) Dual therapy 279 (46.0) 530 (43.7) 869 (50.3) 1727 (49.7) Anti-hypertensive therapy no. (%) 590 (97.2) 1186 (97.9) 1631 (94.5) 3259 (93.8) Angiotensin-converting enzyme 502 (82.7) 1031 (85.1) 1366 (79.1) 2766 (79.6) inhibitors/angiotensin receptor blockers Beta-blockers 415 (68.4) 829 (68.4) 1083 (62.7) 2226 (64.1) Diuretics 355 (58.5) 710 (58.6) 633 (36.7) 1336 (38.5) Calcium channel blockers 227 (37.4) 446 (36.8) 561 (32.5) 1082 (31.2) Mineralocorticoid receptor 48 (7.9) 119 (9.8) 88 (5.1) 186 (5.4) antagonists Renin inhibitors 5 (0.8) 12 (1.0) 14 (0.8) 15 (0.4) Other 70 (11.5) 144 (11.9) 121 (7.0) 239 (6.9) Lipid-lowering therapy no. (%) 496 (81.7) 1024 (84.5) 1368 (79.3) 2795 (80.5) Statins 461 (75.9) 966 (79.7) 1312 (76.0) 2663 (76.7) Fibrates 80 (13.2) 173 (14.3) 119 (6.9) 258 (7.4) Ezetimibe 31 (5.1) 43 (3.5) 50 (2.9) 146 (4.2) Niacin 15 (2.5) 22 (1.8) 20 (1.2) 69 (2.0) Other 72 (11.9) 127 (10.5) 103 (6.0) 238 (6.9) 15

17 Anti-coagulants no. (%) 552 (90.9) 1087 (89.7) 1538 (89.1) 3074 (88.5) Acetylsalicylic acid 495 (81.5) 981 (80.9) 1432 (83.0) 2894 (83.3) Clopidogrel 56 (9.2) 133 (11.0) 193 (11.2) 361 (10.4) Vitamin K antagonists 63 (10.4) 100 (8.3) 93 (5.4) 166 (4.8) Systolic blood pressure mmhg 136.4± ± ± ±16.6 Diastolic blood pressure mmhg 74.6± ± ± ±9.5 Total cholesterol mg/dl** 163.0± ± ± ±44.4 Low density lipoprotein cholesterol 85.0± ± ± ±36.0 mg/dl High density lipoprotein cholesterol 42.9± ± ± ±11.7 mg/dl** Triglycerides mg/dl** 180.4± ± ± ±136.4 Estimated glomerular filtration rate 48.6± ± ± ±17.1 (MDRD) ml/min/1.73m 2 Urine albumin-to-creatinine ratio no. (%) <30 mg/g 283 (46.6) 566 (46.7) 1099 (63.7) 2223 (64.0) 30 to 300 mg/g 205 (33.8) 411 (33.9) 470 (27.2) 926 (26.7) >300 mg/g 115 (18.9) 223 (18.4) 145 (8.4) 286 (8.2) Missing 4 (0.7) 12 (1.0) 12 (0.7) 38 (1.1) * Plus minus values are means ± SD. Body mass index is the weight in kilograms divided by the square of the height in meters. Information was not available for one patient in the placebo group with 60 ml/min/1.73m 2 at baseline. Information was not available for one patient in the placebo group and one patient in the empagliflozin 25 mg group with 60 ml/min/1.73m 2 at baseline. Based on the narrow standardized MedDRA query cardiac failure. ǁ Information was not available for one patient in the empagliflozin 10 mg group with 60 ml/min/1.73m 2 at baseline. ** Placebo n=598 and empagliflozin n=1202 for patients with egfr <60 ml/min/1.73m 2 at baseline; placebo n=1711 and empagliflozin n=3423 for patients with egfr 60 ml/min/1.73m 2 at baseline. Placebo n=598 and empagliflozin n=1201 for patients with egfr <60 ml/min/1.73m 2 at baseline; placebo n=1711 and empagliflozin n=3421 for patients with egfr 60 ml/min/1.73m 2 at baseline. Post-hoc assessment: p<0.05 for difference between empagliflozin and placebo based on Chi-square test for binary/categorical variables or t-test for continuous variables. MDRD, Modification of Diet in Renal Disease. MedDRA, Medical Dictionary for Regulatory Activities. 16

18 Table S2. Cardiovascular medications introduced post-baseline in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline Patients with egfr <60 ml/min/1.73m 2 at baseline Placebo Empagliflozin Patients with egfr 60 ml/min/1.73m 2 at baseline Placebo Empagliflozin (N = 607) (N = 1212) (N = 1726) (N = 3473) Anti-hypertensive therapies no. (%) 359 (59.1) 624 (51.5) 831 (48.1) 1463 (42.1) Angiotensin-converting enzyme 202 (33.3) 359 (29.6) 500 (29.0) 864 (24.9) inhibitors/angiotensin receptor blockers Beta-blockers 136 (22.4) 256 (21.1) 345 (20.0) 602 (17.3) Diuretics 227 (37.4) 327 (27.0) 381 (22.1) 572 (16.5) Calcium channel blockers 137 (22.6) 231 (19.1) 344 (19.9) 441 (12.7) Mineralocorticoid receptor 54 (8.9) 64 (5.3) 82 (4.8) 113 (3.3) antagonists Renin inhibitors 2 (0.3) 4 (0.3) 4 (0.2) 5 (0.1) Other 62 (10.2) 106 (8.7) 103 (6.0) 168 (4.8) Lipid-lowering therapies no. (%) 207 (34.1) 354 (29.2) 512 (29.7) 1012 (29.1) Statins 169 (27.8) 289 (23.8) 432 (25.0) 856 (24.6) Fibrates 41 (6.8) 53 (4.4) 87 (5.0) 158 (4.5) Ezetimibe 17 (2.8) 25 (2.1) 32 (1.9) 69 (2.0) Niacin 5 (0.8) 7 (0.6) 10 (0.6) 16 (0.5) Other 24 (4.0) 35 (2.9) 47 (2.7) 74 (2.1) Anti-coagulants no. (%) 213 (35.1) 391 (32.3) 495 (28.7) 949 (27.3) Acetylsalicylic acid 127 (20.9) 238 (19.6) 327 (18.9) 602 (17.3) Clopidogrel 36 (5.9) 82 (6.8) 98 (5.7) 179 (5.2) Vitamin K antagonists 43 (7.1) 60 (5.0) 59 (3.4) 99 (2.9) Patients treated with 1 dose of study drug. Cardiovascular medications introduced post-baseline irrespective of study medication intake. MDRD, Modification of Diet in Renal Disease. 17

19 Table S3. Composite microvascular outcome with empagliflozin compared with placebo Placebo No. with event/ analyzed (%) Rate/1000 patient-yr No. with event/ analyzed (%) Empagliflozin Rate/1000 patient-yr Hazard ratio (95% CI) p-value Composite microvascular 424/2068 (20.5) /4132 (14.0) (0.54, 0.70) <0.001 outcome Initiation of laser 29/2333 (1.2) /4687 (0.9) (0.43, 1.12) therapy for retinopathy Vitreous hemorrhage 16/2333 (0.7) /4687 (0.6) (0.51, 1.71) Diabetes-related 2/2333 (0.1) 0.3 4/4687 (0.1) 0.3 blindness* Incident or worsening nephropathy 388/2061 (18.8) /4124 (12.7) (0.53, 0.70) <0.001 Prespecified Cox regression analyses in patients treated with 1 dose of study drug. *Hazard ratio and 95% CI were not analyzed as the total number of patients with events was <14. 18

20 Table S4. Incident or worsening nephropathy and incident or worsening nephropathy or cardiovascular death: pre-specified analysis and post-hoc sensitivity analysis Incident or worsening nephropathy Placebo Empagliflozin Hazard ratio No. with event/ Rate/1000 No. with event/ Rate/1000 (95% CI) analyzed (%) patient-yr analyzed (%) patient-yr p-value Pre-specified analysis* 388/2061 (18.8) /4124 (12.7) (0.53, 0.70) <0.001 Sensitivity analysis 388/2333 (16.6) /4687 (11.2) (0.53, 0.69) <0.001 Incident or worsening nephropathy or cardiovascular death Pre-specified analysis* 497/2102 (23.6) /4170 (16.2) (0.55, 0.69) <0.001 Sensitivity analysis 497/2333 (21.3) /4687 (14.4) (0.54, 0.69) <0.001 * Patients treated with 1 dose of study drug not considering patients with macroalbuminuria at baseline and/or patients without baseline and/or post-baseline serum creatinine measurements and/or patients without post-baseline urine albumin-to-creatinine ratio measurements (unless they experienced at least one of the other components of the composite renal outcome). All patients treated with 1 dose of study drug. 19

21 Table S5. Incident or worsening nephropathy and incident or worsening nephropathy or cardiovascular death with empagliflozin compared with placebo in patients with prevalent kidney disease defined as egfr (MDRD) <60 ml/min/1.73m 2 and/or macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline Placebo No. with event/ analyzed (%) Rate/1000 patient-yr Empagliflozin No. with event/ Rate/1000 analyzed (%) patient-yr Hazard ratio (95% CI) p-value Incident or worsening 161/507 (31.8) /998 (20.7) (0.47, 0.71) <0.001 nephropathy Incident or worsening nephropathy or cardiovascular death 213/539 (39.5) /1039 (27.9) (0.53, 0.76) <0.001 Post-hoc Cox regression analyses in patients with prevalent kidney disease treated with 1 dose of study drug. egfr, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease. 20

22 Table S6. Adverse events in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline. Event Patients with egfr (MDRD) <60 ml/min/1.73m 2 at baseline Placebo Pooled empagliflozin (N = 607) (N = 1212) No. (%) Rate per No. (%) Rate per with one or 100-patient with one or 100-patient more event years more event years Patients with egfr (MDRD) 60 ml/min/1.73m 2 at baseline Placebo Pooled empagliflozin (N = 1726) (N = 3473) No. (%) Rate per No. (%) Rate per with one or 100-patient with one or 100-patient more event years more event years Any adverse event 577 (95.1) (91.3) (90.5) (89.9) Rate ratio (95% CI) 0.70 ( ) 0.88 ( ) Severe adverse event 208 (34.3) (29.7) (22.2) (21.3) 9.1 Rate ratio (95% CI) 0.81 ( ) 0.92 ( ) Serious adverse event 321 (52.9) (45.5) (38.6) (35.6) 17.0 Rate ratio (95% CI) 0.78 ( ) 0.87 ( ) Death 40 (6.6) (5.6) (4.6) (3.1) 1.2 Rate ratio (95% CI) 0.82 ( ) 0.66 ( ) Adverse event leading to 167 (27.5) (22.9) (16.6) (15.4) 6.2 discontinuation Rate ratio (95% CI) 0.79 ( ) 0.90 ( ) Confirmed hypoglycemic 233 (38.4) (32.3) (24.2) (26.3) 12.8 adverse event* Rate ratio (95% CI) 0.78 ( ) 1.10 ( ) Requiring assistance 18 (3.0) (1.9) (1.0) (1.2) 0.4 Rate ratio (95% CI) 0.62 ( ) 1.06 ( ) Event consistent with urinary tract infection 132 (21.7) (22.9) (16.9) (16.2) 6.9 Rate ratio (95% CI) 1.06 ( ) 0.92 ( ) 21

23 Complicated urinary tract 17 (2.8) (3.1) (1.4) (1.3) 0.5 infection Rate ratio (95% CI) ( ) ( ) Event consistent with genital 10 (1.6) (5.3) (1.9) (6.8) 2.7 infection Rate ratio (95% CI) ( ) ( ) Event consistent with volume 49 (8.1) (6.7) (3.8) (4.5) 1.8 depletion Rate ratio (95% CI) ( ) ( ) Acute renal failure ǁ 87 (14.3) (11.2) (3.9) (3.2) 1.2 Rate ratio (95% CI) 0.75 ( ) Acute kidney injury 22 (3.6) (2.1) (0.9) (0.5) 0.2 Diabetic ketoacidosis** 1 (0.2) (0.2) (0.1) <0.1 Thromboembolic event 7 (1.2) (1.1) (0.8) (0.5) ( ) Rate ratio (95% CI) 0.89 ( ) 0.63 ( ) Bone fracture 32 (5.3) (4.7) (3.4) (3.5) 1.4 Rate ratio (95% CI) 0.86 ( ) 0.99 ( ) Hyperkalemia 42 (6.9) (3.9) (2.1) (1.3) 0.5 Rate ratio (95% CI) 0.53 ( ) 0.61 ( ) Data are from patients treated with 1 dose of study drug based on events that occurred during treatment or 7 days after the last intake of study drug. Post-hoc assessments. * Plasma glucose 70 mg/dl and/or requiring assistance. Based on 79 MedDRA preferred terms. Pyelonephritis, urosepsis or serious adverse event consistent with urinary tract infection. Based on 88 MedDRA preferred terms. Based on 8 MedDRA preferred terms. ǁ Based on the narrow standardized MedDRA query acute renal failure. ** Based on 4 MedDRA preferred terms. Incidence rate ratio and 95% confidence interval not calculated due to low number of events. Based on 1 standardized MedDRA query Based on 62 MedDRA preferred terms. Based on 2 MedDRA preferred terms. egfr, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease. 22

24 Table S7. Complicated urinary tract infections by MedDRA preferred term in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline Patients with egfr (MDRD) <60 ml/min/1.73m 2 at baseline Patients with egfr (MDRD) 60 ml/min/1.73m 2 at baseline Placebo (N = 607) Empagliflozin (N = 1212) Placebo (N = 1726) Empagliflozin (N = 3473) no. (%) with one or more event Complicated urinary tract infection 17 (2.8) 37 (3.1) 24 (1.4) 45 (1.3) Urinary tract infection 7 (1.2) 15 (1.2) 9 (0.5) 14 (0.4) Urosepsis 2 (0.3) 9 (0.7) 1 (0.1) 8 (0.2) Pyelonephritis 2 (0.3) 4 (0.3) 2 (0.1) 9 (0.3) Pyelonephritis chronic 4 (0.7) 5 (0.4) 6 (0.3) 5 (0.1) Pyelonephritis acute 1 (0.2) 4 (0.3) 5 (0.3) 4 (0.1) Cystitis (0.1) 0 Kidney infection 2 (0.3) 1 (0.1) 0 3 (0.1) Urinary tract infection fungal 0 2 (0.2) 0 1 (<0.1) Cystitis bacterial (0.1) 0 Escherichia urinary tract infection 1 (0.2) Urinary tract infection (<0.1) pseudomonal Cystitis glandularis (<0.1) Cystitis hemorrhagic (0.1) 0 Nephritis (<0.1) Data are from patients treated with 1 dose of study drug based on events that occurred during treatment or 7 days after the last intake of study medication. Complicated urinary tract infection defined as pyelonephritis, urosepsis or serious adverse event consistent with urinary tract infection. MedDRA, Medical Dictionary for Regulatory Activities. egfr, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease. 23

25 Table S8. Changes in clinical laboratory parameters in patients with egfr (MDRD) <60 and 60 ml/min/1.73m 2 at baseline. Patients with egfr (MDRD) <60 ml/min/1.73m 2 at baseline Patients with egfr (MDRD) 60 ml/min/1.73m 2 at baseline Placebo Empagliflozin Placebo Empagliflozin Baseline Change from baseline Baseline Change from baseline Baseline Change from baseline Baseline Change from baseline Hematocrit, % 40.3 ± ± ± ± ± ± ± ± 5.2 Hemoglobin, g/dl 13.1 ± ± ± ± ± ± ± ± 1.3 Aspartate 15 ± 12 0 ± ± 10-1 ± ± 12 1 ± ± 10 0 ± 23 aminotransferase, U/L Alanine aminotransferase, 17 ± 13-1 ± ± 10-1 ± ± 14 0 ± ± 12-2 ± 19 U/L Alkaline phosphatase, U/L 66 ± 35 8 ± ± 36 6 ± ± 31 4 ± ± 31 2 ± 26 Electrolytes Sodium, meq/l 141 ± 2 0 ± ± 2 0 ± ± 2 0 ± ± 2 0 ± 2 Potassium, meq/l 4.4 ± ± ± ± ± ± ± ± 0.4 Calcium, mg/dl 9.8 ± ± ± ± ± ± ± ± 0.5 Magnesium, meq/l 1.7 ± ± ± ± ± ± ± ± 0.2 Chloride, meq/l 102 ± 2-1 ± ± 2-1 ± ± 2-1 ± ± 2-1 ± 2 Phosphate, mg/dl 3.7 ± ± ± ± ± ± ± ± 0.3 Plus-minus values are means ± SD and data are normalized to a standard reference range. Changes from baseline are the last measurement 3 days after the last intake of study medication. Data are from patients treated with 1 dose of study drug with a baseline and on-treatment measurement. Conversion factors: sodium, potassium, chloride and phosphate: 1 meq/l = 1 mmol/l; calcium: 1 mg/dl = 0.25 mmol/l; magnesium: 1 meq/l = 0.5 mmol/l. egfr, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease. Hematocrit: Placebo n=587 and empagliflozin n=1141 for patients with egfr <60 ml/min/1.73m 2 at baseline; placebo n=1671 and empagliflozin n=3355 for patients with egfr 60 ml/min/1.73m 2 at baseline. Hemoglobin: Placebo n=589 and empagliflozin n=1145 for patients with egfr <60 ml/min/1.73m 2 at baseline; placebo n=1674 and empagliflozin n=3366 for patients with egfr 60 ml/min/1.73m 2 at baseline. 24

26 Aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase: Placebo n=603 and empagliflozin n=1182 for patients with egfr <60 ml/min/1.73m 2 at baseline; placebo n=1710 (or n=1709 for aspartate aminotransferase) and empagliflozin n=3430 for patients with egfr 60 ml/min/1.73m 2 at baseline. Electrolytes: Placebo n=588 and empagliflozin n=1150 (or n=1151 for potassium) for patients with egfr <60 ml/min/1.73m 2 at baseline; placebo n=1673 (or n=1672 for potassium) and empagliflozin n=3370 for patients with egfr 60 ml/min/1.73m 2 at baseline. 25

egfr > 50 (n = 13,916)

egfr > 50 (n = 13,916) Saxagliptin and Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus and Moderate or Severe Renal Impairment: Observations from the SAVOR-TIMI 53 Trial Supplementary Table 1. Characteristics according