Table 4.
Empagliflozin combination therapy studies: key safety data
| Study | Study details | Regimen details | N | Treatment and dose (mg/d) | Safety parameters (Number and percentage of patients with a special interest adverse event)
|
|||
|---|---|---|---|---|---|---|---|---|
| Hypoglycemia, n (%) | Urinary tract infection, n (%) [males and females, n (%) if stated] | Genital infection, n (%) [males and females, n (%) if stated] | Volume depletion, n (%) | |||||
| Add-on to stable therapy | ||||||||
| Rosenstock et al18 | Phase II, 12 wk | Add-on to stable metformin: MET ≥1,500 mg/d or MTD | ||||||
| 71 | Pbo | 0 | 2 (2.8) | 0 | Not reported | |||
| 71 | EMPA 1 | 0 | 2 (2.8) | 1 (1.4) | Not reported | |||
| 71 | EMPA 5 | 3 (4.2) | 2 (2.8) | 4 (5.6) | Not reported | |||
| 71 | EMPA 10 | 0 | 3 (4.2) | 7 (9.9) | Not reported | |||
| 70 | EMPA 25 | 0 | 4 (5.7) | 0 | Not reported | |||
| 70 | EMPA 50 | 1 (1.4) | 3 (4.3) | 2 (2.9) | Not reported | |||
| 71 | O/L SITA | 2 (2.8) | 3 (4.2) | 2 (2.8) | Not reported | |||
| Häring et al19 | Phase III, 24 wk | Add-on to stable metformin: MET ≥1,500 mg/d or MTD | ||||||
| 207 | Pbo | 1 (0.5) | 10 (4.9) [M3/116 (2.6), F7/91 (7.7)] |
0 [M0/116, F0/91] |
Not reported | |||
| 217 | EMPA 10 | 4 (1.8) | 11 (5.1) [M0/125, F11/92 (12.0)] |
8 (3.7) [M1/125 (0.8), F7/92 (7.6)] |
Not reported | |||
| 213 | EMPA 25 | 3 (1.4) | 12 (5.6) [M1/120 (0.8), F11/93 (11.8)] | 10 (4.7) [M1/120 (0.8), F9/93 (9.7)] |
Not reported | |||
| 69 | O/L EMPA 25 (HbA1c >10.0%) | 2 (2.9) | 5 (7.2) [M1/41 (2.4), F4/28 (14.3)] |
1 (1.4) [M0/41, F1/28 (3.6)] |
Not reported | |||
| Ridderstråle et al20 | Phase III, 104 wk | Add-on to stable metformin: MET ≥1,500 mg/d or MTD | ||||||
| 52 wk | 780 | GLIM 1–4 | Not reported | Not reported | Not reported | Not reported | ||
| 104 wk | GLIM 1–4 | 195 (25) | 102 (13) [M21/421 (5), F81/359, (23)] |
17 (2) [M5/421 (1), F12/359 (3)] |
8 (1) | |||
| 52 wk | 765 | EMPA 25 | Not reported | Not reported | Not reported | Not reported | ||
| 104 wk | EMPA 25 | 32 (4) | 105 (14) [M31/432, (7), F74/333 (22)] |
90 (12) [M41/432, (9), F49/333 (15)] |
11 (1) | |||
| Ross et al29 | Phase II, 16 wk | Add-on to stable metformin: MET ≥1,500 mg/d | ||||||
| 107 | Pbo | 1 (0.9) | 4 (3.7) [M1 (1.8), F3 (5.8)] |
3 (2.8) [M1 (1.8), F2 (3.8)] |
0 | |||
| 219 | EMPA 12.5 mg twice daily |
0 | 13 (5.9) [M6 (4.8), F7 (7.5)] |
9 (4.1) [M3 (2.4), F6 (6.5)] |
1 (0.5) | |||
| 218 | EMPA 25 mg once daily |
1 (0.5) | 12 (5.5) [M3 (2.5), F9 (9.0)] |
9 (4.1) [M1 (0.8), F8 (8.0)] |
0 | |||
| 219 | EMPA 5 mg twice daily |
1 (0.5) | 17 (7.8) [M4 (3.3), F13 (13.5)] |
8 (3.7) [M3 (2.4), F5 (5.2)] |
0 | |||
| 220 | EMPA 10 mg once daily | 1 (0.5) | 21 (9.5) [M5 (4.5), F16 (14.7)] |
7 (3.2) [M2 (1.8), F5 (4.6)] |
2 (0.9) | |||
| Kovacs et al21 | Phase III, 24 wk | Add-on to stable pioglitazone ± metformin: PIO ≥30 mg/d, MET ≥1,500 mg/d or MTD | ||||||
| 165 | Pbo | 3 (1.8) | 27 (16.4) [M6/73 (8.2), F21/92 (22.8)] |
4 (2.4) [M1/73 (1.4), F3/92 (3.3)] |
Not reported | |||
| 165 | EMPA 10 | 2 (1.2) | 28 (17.0) [M3/83 (3.6), F25/82 (30.5)] |
14 (8.5) [M6/83 (7.2), F8/82 (9.8)] |
Not reported | |||
| 168 | EMPA 25 | 4 (2.4) | 20 (11.9) [M2/85 (2.4), F18/83 (21.7)] |
6 (3.6) [M1/85 (1.2), F5/83 (6.0)] |
Not reported | |||
| Häring et al22 | Phase III, 24 wk | Add-on to stable metformin plus sulfonylurea: MET ≥1,500 mg/d or MTD, SU ≥half max labeled dose or MTD | ||||||
| 225 | Pbo | 19 (8.4) | 18 (8.0) [M3/112 (2.7), F15/113 (13.3)] |
2 (0.9) [M1/112 (0.9), F1/113 (0.9)] |
Not reported | |||
| 225 | EMPA 10 | 36 (16.1) | 23 (10.3) [M3/113 (2.7), F20/112 (18.0)] |
6 (2.7) [M1/113 (0.9), F5/112 (4.5)] |
Not reported | |||
| 216 | EMPA 25 | 25 (11.5) | 18 (8.3) [M0/114, F18/102 (17.5)] |
5 (2.3) [M1/114 (0.9), F4/102 (3.9)] |
Not reported | |||
| 101 | O/L EMPA 25 (HbA1c >10.0) |
7 (6.9) | 3 (3.0) [M0/54, F3/47 (6.4)] |
2 (2.0) [M1/54 (1.9), F1/47 (2.1)] |
Not reported | |||
| Rosenstock et al23 | Phase III, 52 wk | Add-on to MDI of insulin ± metformin: INS titrated for treat-to-target (wk 19–40) | ||||||
| 188 | Pbo | 109 (58.0) | 29 (15.4) [M0/75, F29/113 (25.7)] |
3 (1.6) [M1/75 (1.3), F2/113 (1.8)] |
Not reported | |||
| 186 | EMPA 10 | 95 (51.1) | 29 (15.6) [M5/97 (5.2), F24/89 (27.0)] |
8 (4.3) [M1/97 (1.0), F7/89 (7.9)] |
Not reported | |||
| 189 | EMPA 25 | 109 (57.7) | 29 (15.3) [M3/84 (3.6), F26/105 (24.8)] |
18 (9.5) [M7/84 (8.3), F11/105 (10.5)] |
Not reported | |||
| Rosenstock et al30 | Phase II, 78 wk | Add-on to basal insulin ± metformin ± sulfonylurea Insulin unchanged in wk 1–18 | (wk 78) | (wk 78) | (wk 78) | |||
| 170 | Pbo | 60 (35%) | 15 (9%) [M3/90 (3), F12/80 (15)] |
3 (2%) [M0, F3/80 (4)] |
Not reported | |||
| 169 | EMPA 10 | 61 (36%) | 25 (15%) [M5/93 (5), F20/76 (26)] |
13 (8%) [M7/93 (8), F6/76 (8)] |
Not reported | |||
| 155 | EMPA 25 | 56 (36%) | 18 (12%) [M7/93 (8), F11/62 (18)] |
8 (5%) [M4/93 (4), F4/62 (7)] |
Not reported | |||
| Ferrannini et al24 | 78 wk | Extension of two Phase II studies16,18 | ||||||
| Monotherapy | 106 | EMPA 10 | 1 (0.9) | 4 (3.8) [M0/49, F4/57 (7.0)] |
5 (4.7) [M2/49 (4.1), F3/57 (5.3)] |
Not reported | ||
| 109 | EMPA 25 | 2 (1.8) | 7 (6.4) [M4/57 (7.0), F3/52 (5.8)] |
6 (5.5) [M3/57 (5.3), F3/52 (5.8)] |
Not reported | |||
| 56 | MET ≤1,000 mg twice daily or MTD | 2 (3.6) | 2 (3.6) [M0/28, F2/28 (7.1)] |
1 (1.8) [M0/28, F1/28 (3.6)] |
Not reported | |||
| Add-on to metformin | 166 | EMPA 10 | 3 (1.8) | 15 (9.0) [M2/83 (2.4), F13/83 (15.7)] |
5 (3.0) [M2/83 (2.4), F3/83 (3.6)] |
Not reported | ||
| 166 | EMPA 25 | 4 (2.4) | 21 (12.7) [M3/88 (3.4), F18/78 (23.1)] |
6 (3.6) [M3/88 (3.4), F3/78 (3.8)] |
Not reported | |||
| 56 | SITA 100 | 2 (3.6) | 7 (12.5) [M3/29 (10.3), F4/27 (14.8)] |
0 [M0/29, F0/27] |
Not reported | |||
| Single-pill combination therapy | ||||||||
| Lewin et al25 | Phase III, 52 wk | Treatment-naïve | ||||||
| 136 | EMPA 25/LINA 5 | 0 | 17 (12.5) [M4 (5.6), F13 (20.3)] |
8 (5.9) [M5 (6.9), F3 (4.7)] |
1 (0.7) | |||
| 136 | EMPA 10/LINA 5 | 0 | 21 (15.4) [M5 (6.8), F16 (25.8)] |
4 (2.9) [M1 (1.4), F3 (4.8)] |
3 (2.2) | |||
| 135 | EMPA 25 | 1 (0.7) | 14 (10.4) [M3 (3.8), F11 (19.3)] |
6 (4.4) [M1 (1.3), F5 (8.8)] |
0 | |||
| 135 | EMPA 10 | 4 (3.0) | 22 (16.3) [M6 (9.2), F16 (22.9)] |
7 (5.2) [M2 (3.1), F5 (7.1)] |
0 | |||
| 135 | LINA 5 | 1 (0.7) | 14 (10.4) [M2 (2.7), F12 (20.0)] |
4 (3.0) [M1 (1.3), F3 (5.0)] |
0 | |||
| DeFronzo et al26 | Phase III, 52 wk | Add-on to stable metformin: MET ≥1,500 mg/d or MTD | ||||||
| 134 | EMPA 25/LINA 5 | 5 (3.6) | 14 (10.2) [M2/72 (2.7), F12/62 (18.8)] |
3 (2.2) [M2/72 (2.7), F1/62 (1.6)] |
1 (0.7) | |||
| 135 | EMPA 10/LINA 5 | 3 (2.2) | 13 (9.6) [M2/83 (2.4), F11/52 (21.2)] |
8 (5.9) [M2/83 (2.4), F6/52 (11.5)] |
2 (1.5) | |||
| 140 | EMPA 25 | 5 (3.5) | 19 (13.5) [M2/65 (3.0), F17/75 (22.7)] |
12 (8.5) [M3/65 (4.5), F9/75 (12.0)] |
2 (1.4) | |||
| 137 | EMPA 10 | 2 (1.4) | 16 (11.4) [M3/78 (3.7), F13/59 (22.0)] |
11 (7.9) [M5/78 (6.2), F6/59 (10.2)] |
1 (0.7) | |||
| 128 | LINA 5 | 3 (2.3) | 20 (15.2) [M3/64 (4.5), F17/64 (26.2)] |
3 (2.3) [M2/64 (3.0), F1/64 (1.5)] |
4 (3.0) | |||
| Special populations | ||||||||
| Tikkanen et al27 | Phase III, 12 wk, adults with T2DM and hypertension | Treatment-naïve or on stable anti-diabetes treatment (oral or other) | ||||||
| 272 | Pbo | 13 (4.8) | 10 (3.7) [M1 (0.6), F9 (8.7)] |
1 (0.4) [M1 (0.6), F0] |
1 (0.4) | |||
| 276 | EMPA 10 | 18 (6.5) | 11 (4.0) [M1 (0.6), F10 (9.5)] |
14 (5.1) [M8 (4.7), F6 (5.7)] |
1 (0.4) | |||
| 276 | EMPA 25 | 17 (6.2) | 13 (4.7) [M4 (2.6), F9 (7.4)] |
15 (5.4) [M6 (3.9), F9 (7.4)] |
0 | |||
| Barnett et al28 | Phase III, 52 wk, adults with T2DM and CKD | Add-on to stable anti-diabetes treatment (oral or other) | ||||||
| Stage 2 CKD | 95 | Pbo | 23 (24.2) | 15 (15.8) [M5/56 (8.9), F10/39 (25.6)] |
6 (6.3) [M2/56 (3.6), F4/39 (10.3)] |
1 (1.1) | ||
| 98 | EMPA 10 | 26 (26.5) | 14 (14.3) [M5/60 (8.3), F9/38 (23.7)] |
7 (7.1) [M6/60 (10.0), F1/38 (2.6)] |
1 (1.0) | |||
| 97 | EMPA 25 | 22 (22.7) | 9 (9.3) [M2/61 (3.3), F7/36 (19.4)] |
5 (5.2) [M0/61, F5/36 (13.9)] |
0 | |||
| Stage 3 CKD | 187 | Pbo | 53 (28.3) | 29 (15.5) [M4/106 (3.8), F25/81 (30.9)] |
2 (1.1) [M1/106 (0.9), F1/81 (1.2)] |
5 (2.7) | ||
| 187 | EMPA 25 | 52 (27.8) | 31 (16.6) [M6/107 (5.6), F25/80 (31.3)] |
5 (2.7) [M2/107 (1.9), F3/80 (3.8)] |
7 (3.7) | |||
| Stage 4 CKD | 37 | Pbo | 12 (32.4) | 3 (8.1) [M0/19, F3/18 (16.7)] |
0 [M0/19, F0/18] |
2 (5.4) | ||
| 37 | EMPA 25 | 14 (37.8) | 7 (18.9) [M2/21 (9.5), F5/16 (31.3)] |
1 (2.7) [M0/21, F1/16 (6.3)] |
2 (5.4) | |||
Note: Number of male and female patients in the safety set was not available for all studies; in those cases only percentages are shown. MET dosing: 1000 mg/d for 4 weeks, thereafter increased to 1000 mg twice daily, or up to maximum tolerated dose, if needed.
Abbreviations: CKD, chronic kidney disease; EMPA, empagliflozin; F, female; GLIM, glimepiride; HbA1c, glycated hemoglobin; INS, insulin; LINA, linagliptin; M, male; MDI, multiple daily injections; MET, metformin; MTD, maximum tolerated dose; O/L, open label; Pbo, placebo; PIO, pioglitazone; SITA, sitagliptin; SU, sulfonylurea; T2DM, type 2 diabetes mellitus.