Table 3: Safety and tolerability of empagliflozin in patients with type 2 diabetes (pooled analysis of phase I–III trials).
| Placebo (n=4,203) | Empagliflozin 10 mg (n=4,22l) | Empagliflozin 25 mg (n=4,196) | ||||
|---|---|---|---|---|---|---|
| n (%) | Rate/100 patient-years | n (%) | Rate/100 patient-years | n (%) | Rate/100 patient-years | |
| ≥1 AE | 3,449 (82.1) | 195.4 | 3,401 (80.6) | 167.2 | 3,383 (80.6) | 163.6 |
| ≥1 drug-related AE | 921 (21.9) | 14.9 | 1,144 (27.1) | 18.6 | 1,117 (26.6) | 18.1 |
| ≥1 AE-related withdrawal | 540 (12.8) | 7.6 | 490 (11.6) | 6.5 | 484 (11.5) | 6.4 |
| ≥1 severe AE | 718 (17.1) | 10.8 | 634 (15.0) | 8.9 | 682 (16.3) | 9.6 |
| ≥1 serious AE | 1,150 (27.4) | 19.2 | 1,020 (24.2) | 15.5 | 1,052 (25.1) | 16.5 |
| Fatal AE | 122 (2.9) | 1.6 | 100 (2.4) | 1.3 | 83 (2.0) | 1.1 |
| AEs with frequency ≥5% by MedDRA preferred term: | ||||||
| Hypoglycaemia | 956 (22.7) | 16.1 | 977 (23.1) | 15.9 | 952 (22.7) | 15.5 |
| Hyperglycaemia | 709 (16.9) | 11.0 | 346 (8.2) | 4.7 | 306 (7.3) | 4.1 |
| Urinary tract infection | 523 (12.4) | 7.7 | 528 (12.5) | 7.4 | 510 (12.2) | 7.2 |
| Nasopharyngitis | 424 (10.1) | 6.1 | 417 (9.9) | 5.7 | 408 (9.7) | 5.6 |
| URTI | 292 (6.9) | 4.2 | 285 (6.8) | 3.8 | 288 (6.9) | 3.9 |
| Hypertension | 291 (6.9) | 4.1 | 205 (4.9) | 2.7 | 218 (5.2) | 2.9 |
| Back pain | 238 (5.7) | 3.3 | 232 (5.5) | 3.1 | 253 (6.0) | 3.4 |
| Dizziness | 208 (4.9) | 2.9 | 246 (5.8) | 3.3 | 250 (6.0) | 3.4 |
| Diarrhoea | 247 (5.9) | 3.5 | 219 (5.2) | 2.9 | 212 (5.1) | 2.8 |
| Bronchitis | 221 (5.3) | 3.1 | 185 (4.4) | 2.4 | 163 (3.9) | 2.1 |
| Influenza | 219 (4.7) | 3.1 | 173 (4.1) | 2.3 | 199 (4.7) | 2.6 |
| Arthralgia | 196 (4.7) | 2.7 | 180 (4.3) | 2.4 | 213 (5.1) | 2.8 |
| Hypoglycaemic events by glucose lowering medication: | ||||||
| Insulin use | ||||||
| No | 230/2,595 | 5.9 | 240/2,612 | 5.9 | 251/2,607 | 6.1 |
| Yes | 676/1,608 | 31.7 | 683/1,609 | 32.1 | 659/1,589 | 31.4 |
| Sulfonylurea use | ||||||
| No | 595/2,781 | 16.9 | 575/2,801 | 15.4 | 571/2,748 | 15.7 |
| Yes | 311/1,422 | 12.3 | 348/1,420 | 14.0 | 339/1,448 | 13.0 |
| Metformin use | ||||||
| No | 257/1,275 | 17.3 | 251/1,259 | 15.5 | 220/1,255 | 13.5 |
| Yes | 649/2,928 | 14.2 | 672/2,962 | 14.6 | 690/2,941 | 14.9 |
| Metformin alone use | ||||||
| No | 885/3,607 | 17.1 | 903/3,583 | 17.4 | 889/3,594 | 16.8 |
| Yes | 21/596 | 2.4 | 20/638 | 1.9 | 21/602 | 2.2 |
| Urinary tract infection | 629 | 9.5 | 639 | 9.2 | 607 | 8.7 |
| Men | 193/2,700 | 4.0 | 217/2,731 | 4.3 | 206/2,745 | 4.0 |
| Women | 436/1,503 | 23.9 | 422/1,490 | 21.7 | 401/1,451 | 21.8 |
| Aged <50 years | 75/531 | 12.4 | 59/533 | 7.9 | 64/544 | 8.8 |
| Aged 50–<65 years | 281/2,206 | 7.9 | 299/2,176 | 8.3 | 257/2,154 | 7.1 |
| Aged 65–<75 years | 208/1,184 | 10.5 | 204/1,235 | 9.4 | 222/1,213 | 10.2 |
| Aged ≥75 years | 65/282 | 13.0 | 77/277 | 16.8 | 64/285 | 13.6 |
| Genital infection | 67 | 0.9 | 259 | 3.5 | 251 | 3.4 |
| Men | 33/2,700 | 0.7 | 135/2,731 | 2.6 | 107/2,745 | 2.0 |
| Women | 34/1,503 | 1.5 | 124/1,490 | 5.2 | 144/1,451 | 6.6 |
| Aged <50 years | 14/531 | 2.1 | 44/533 | 5.8 | 37/544 | 4.8 |
| Aged 50–<65 years | 29/2,206 | 0.8 | 135/2,176 | 3.5 | 129/2,154 | 3.4 |
| Aged 65–<75 years | 20/1,184 | 0.9 | 63/1,235 | 2.6 | 70/1,213 | 2.9 |
| Aged ≥75 years | 4/282 | 0.7 | 17/277 | 3.2 | 15/285 | 2.8 |
| Volume depletion | 126 | 1.7 | 138 | 1.8 | 142 | 1.9 |
| <50 | 5/351 | 0.7 | 5/533 | 0.6 | 10/544 | 1.3 |
| 60–<65 | 48/2,206 | 1.2 | 48/2,176 | 1.2 | 53/2,154 | 1.4 |
| Aged 65–<75 years | 60/1,184 | 2.8 | 68/1,235 | 2.9 | 63/1,213 | 2.6 |
| Aged ≥75 years | 13/282 | 2.3 | 14/277 | 3.2 | 16/285 | 3.0 |
| Bone fractures | 123 | 1.7 | 119 | 1.6 | 105 | 1.4 |
| eGFR at baseline, mL/min/1.73 m2: | ||||||
| ≥90 | 15/1,172 | 0.8 | 27/1,204 | 1.4 | 12/1,233 | 1.1 |
| 60–<90 | 70/2,298 | 1.8 | 57/2,285 | 1.4 | 53/2,216 | 1.3 |
| 45–<60 | 30/529 | 2.8 | 23/530 | 2.0 | 21/531 | 1.8 |
| 30–<45 | 7/197 | 1.6 | 12/192 | 3.0 | 8/197 | 1.9 |
| <30 | 1/7 | 7.9 | 0/9 | 0 | 0/16 | 0 |
| Cancer events: | 95 | 1.3 | 121 | 1.6 | 119 | 1.5 |
| Onset ≥6 months from start of treatment/participants with exposure ≥6 months | 76/3,159 | 1.4 | 103/3,270 | 1.8 | 86/3,203 | 1.5 |
| Bladder cancer | 2 | 0.0 | 4 | 0.1 | 7 | 0.1 |
| Renal cancer | 5 | 0.1 | 4 | 0.1 | 3 | 0.1 |
| Breast cancer | 4 | 0.1 | 3 | 0.1 | 3 | 0.1 |
| Melanoma | 2 | <0.1 | 4 | 0.1 | 3 | 0.1 |
| Lung cancer | 7 | 0.1 | 11 | 0.2 | 9 | 0.2 |
| Decreased renal function | 159 | 2.2 | 137 | 1.8 | 141 | 1.8 |
| eGFR, mL/min/1.73 m2: | ||||||
| ≥90 | 13/1,172 | 0.7 | 9/1,204 | 0.5 | 10/1,233 | 0.5 |
| 60–<90 | 56/2,298 | 1.4 | 56/2,285 | 1.4 | 53/2,216 | 1.3 |
| 45–<60 | 55/529 | 5.2 | 45/530 | 4.0 | 42/531 | 3.7 |
| 30–<45 | 32/197 | 7.9 | 24/192 | 6.2 | 34/197 | 8.9 |
| <30 | 3/7 | 37.7 | 3/9 | 21.4 | 2/16 | 7.6 |
| Acute kidney injury | 38 | 0.5 | 28 | 0.4 | 24 | 0.3 |
| Hepatic injury | 151 | 2.1 | 106 | 1.4 | 127 | 1.7 |
| Acute pancreatitis | 4 | 0.1 | 1 | <0.1 | 4 | 0.1 |
| Diabetic ketoacidosis | 5 | 0.1 | 5 | 0.1 | 1 | <0.1 |
| Venous thromboembolic events | 23 | 0.3 | 11 | 0.1 | 26 | 0.3 |
| Lower limb amputations | 46 | 46 | - | 48 | ||
| Events potentially related to lower limb amputations: | ||||||
| Peripheral artery obstructive disease events | 96 | - | 98 | - | 112 | - |
| Diabetic foot-related events | 109 | - | 94 | - | 106 | - |
| Relevant infection events | 74 | - | 79 | - | 80 | - |
Reproduced with permission from Kohler et al., 2017.22aIn the opinion of the investigator. bAE that is incapacitating or causing inability to work or to perform usual activities. cAE that results in death, is immediately life-threatening, results in persistent or signficant disability/incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly/birth defect, or is deemed serious for any other reason. dWith or without other glucose-lowering medication. Hypoglycaemic AEs defined as those resulting in plasma glucose of at most 3.9 mmol/L and/or requiring assitance. AE = adverse event; eGFR = estimated glomerular filtration rate; MedDRA = Medical Dictionary for Regulatory Activities; URTI = upper respiratory tract infection.