Table 2.
| Treatment arms | Incidence of AE, n (%) | % of patients with AE leading to trial product discontinuation | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any | Severe or confirmed symptomatic hypoglycemic episode* | Gastrointestinal | Pancreas | Gallbladder | Thyroid | Diabetic retinopathy | Acute kidney Injury | Any AE, n(%) | Gastrointestinal, % | ||||
| Nausea | Vomiting | Diarrhea | Pancreatitis | Pancreatic cancer | |||||||||
| PIONEER 1 | |||||||||||||
| Oral semaglutide 3 mg | 101 (57.7) | 5 (2.9) | 14 (8.0) | 5 (2.9) | 15 (8.6) | 0 | NR | 0 | 1 (0.6%) | 0 | 4 (2.3) | 75 | |
| Oral semaglutide 7 mg | 93 (53.1) | 2 (1.1) | 9 (5.1) | 8 (4.6) | 9 (5.1) | 0 | NR | 0 | 6 (3.4%) | 0 | 7 (4.0) | 57 | |
| Oral semaglutide 14 mg | 99 (56.6) | 1 (0.6) | 28 (16.0) | 12 (6.9) | 9 (5.1) | 0 | NR | 0 | 2 (1.1%) | 1 (0.6) | 13 (7.4) | 69 | |
| Placebo | 99 (55.6) | 1 (0.6) | 10 (5.6) | 4 (2.2) | 4 (2.2) | 0 | NR | 0 | 3 (1.7%) | 1 (0.6) | 4 (2.2) | 25 | |
| PIONEER 2 | |||||||||||||
| Oral semaglutide 14 mg | 289 (70.5) | 7 (1.7) | 81 (19.8) | 30 (7.3) | 38 (9.3) | 1 (0.2) | 0 | NR | 0 | 14 (3.4) | 2 (0.5) | 44 (10.7) | 75 |
| Empagliflozin 25 mg | 283 (69.2) | 8 (2.0) | 10 (2.4) | 7 (1.7) | 13 (3.2) | 1 (0.2) | 0 | NR | 0 | 5 (1.2%) | 1 (0.2) | 18 (4.4) | 17 |
| PIONEER 3 | |||||||||||||
| Oral semaglutide 3 mg | 370 (79.4) | 23 (4.9) | 34 (7.3) | 13 (2.8) | 45 (9.7) | 1 (0.2) | 0 | NR | 0 | 27 (5.8) | 3 (0.6) | 26 (5.6) | 42 |
| Oral semaglutide 7 mg | 363 (78.2) | 24 (5.2) | 62 (13.4) | 28 (6.0) | 53 (11.4) | 1 (0.2) | 0 | NR | 0 | 24 (5.2) | 2 (0.4) | 27 (5.8) | 56 |
| Oral semaglutide 14 mg | 370 (79.6) | 36 (7.7) | 70 (15.1) | 42 (9.0) | 57 (12.3) | 1 (0.2) | 1 (0.2) | NR | 0 | 16 (3.4) | 5 (1.1) | 54 (11.6) | 59 |
| Sitagliptin 100 mg | 388 (83.3) | 39 (8.4) | 32 (6.9) | 19 (4.1) | 37 (7.9) | 1 (0.2) | 1 (0.2) | NR | 0 | 27 (5.8) | 3 (0.6) | 24 (5.2) | 50 |
| PIONEER 4 | |||||||||||||
| Oral semaglutide 14 mg | 229 (80) | 2 (1) | 56 (20) | 25 (9) | 43 (15) | 0 | 0 | NR | 1 (0.4) | 8 (3) | 0 | 31 (11) | 71 |
| Liraglutide 1.8 mg (s.c.) | 211 (74) | 7 (2) | 51 (18) | 13 (5) | 31 (11) | 1 (0.4) | 1 (0.4) | NR | 1 (0.4) | 4 (1) | 1 (0.4) | 26 (9) | 65 |
| Placebo | 95 (67) | 3 (2) | 5 (4) | 3 (2) | 11 (8) | 1 (0.7) | 0 | NR | 0 | 2 (1) | 1 | 5 (4) | 60 |
| PIONEER 5 | |||||||||||||
| Oral semaglutide 14 mg | 122 (75) | 9 (6) | 31 (19) | 19 (12) | 17 (10) | 0 | 0 | NR | 0 | 5 (3) | 3 (1.8) | 24 (15) | 79 |
| Placebo | 109 (68) | 3 (2) | 12 (7) | 6 (4) | 6 (4) | 0 | 0 | NR | 0 | 2 (1) | 1 (0.6) | 8 (5) | 38 |
| PIONEER 6 | |||||||||||||
| Oral semaglutide 14 mg | NR | NR | NR | NR | NR | 1 (0.1) | 0 | NR | 2 (0.1) | 93 (5.8) | 32 (2.0) | 184 (11.6) | 59 |
| Placebo | NR | NR | NR | NR | NR | 3 (0.2) | 0 | NR | 0 | 76 (4.8) | 37 (2.3) | 104 (6.5) | 25 |
| PIONEER 7 | |||||||||||||
| Oral semaglutide (flexible 3, 7 or 14 mg) | 197 (78) | 14 (5.5) | 53 (21) | 14 (6) | 22 (9) | 0 | 0 | NR | 0 | 6 (2.4) | 1 (0.4) | 22 (9) | 64 |
| Sitagliptin 100 mg | 172 (69) | 14 (5.6) | 6 (2) | 3 (1) | 8 (3) | 0 | 0 | NR | 0 | 6 (2.4) | 0 | 8 (3) | 25 |
| PIONEER 8 | |||||||||||||
| Oral semaglutide 3 mg | 137 (74.5) | 52 (28.3) | 21 (11.4) | 11 (6.0) | 16 (8.7) | 0 | 0 | NR | 0 | 7 (3.8) | 2 (1.1) | 13 (7.1) | 69 |
| Oral semaglutide 7 mg | 142 (78.5) | 47 (26.0) | 30 (16.6) | 14 (7.7) | 22 (12.2) | 0 | 0 | NR | 0 | 8 (4.4) | 1 (0.6) | 16 (8.8) | 75 |
| Oral semaglutide 14 mg | 151 (83.4) | 48 (26.5) | 42 (23.2) | 18 (9.9) | 27 (14.9) | 0 | 0 | NR | 0 | 9 (5.0) | 0 | 24 (13.3) | 79 |
| Placebo | 139 (75.5) | 54 (29.3) | 13 (7.1) | 7 (3.8) | 11 (6.0) | 0 | 0 | NR | 0 | 8 (4.3) | 0 | 5 (2.7) | 20 |
| PIONEER 9 | |||||||||||||
| Oral semaglutide 3 mg | 37 (76) | 0 | 2 (4) | NR | 4 (8) | 0 | 0 | NR | 0 | 0 | 0 | 1 (2) | 100 |
| Oral semaglutide 7 mg | 37 (76) | 0 | 5 (10) | NR | 1 (2) | 0 | 0 | NR | 1 | 1 (2.0) | 0 | 1 (2) | 100 |
| Oral semaglutide 14 mg | 34 (71) | 0 | 4 (8) | NR | 3 (6) | 0 | 0 | NR | 0 | 1 (2.1) | 0 | 2 (4) | 100 |
| Liraglutide 0.9 mg (s.c.) | 32 (67) | 2 (4.2) | 0 | NR | 2 (4) | 0 | 0 | NR | 0 | 0 | 0 | 0 | 0 |
| Placebo | 39 (80) | 0 | 1 (2) | NR | 1 (2) | 0 | 0 | NR | 0 | 2 (4.1) | 0 | 0 | 0 |
| PIONEER 10 | |||||||||||||
| Oral semaglutide 3 mg | 101 (77) | 3 (2) | 7 (5) | 3 (2) | 2 (2) | 0 | 0 | 2 (2) | 0 | 9 (7) | 0 | 4 (3) | 50 |
| Oral semaglutide 7 mg | 106 (80) | 3 (2) | 11 (8) | 6 (5) | 2 (2) | 0 | 0 | 1 (1) | 0 | 12 (9) | 0 | 8 (6) | 50 |
| Oral semaglutide 14 mg | 111 (85) | 4 (3) | 12 (9) | 9 (7) | 10 (8) | 0 | 0 | 0 | 0 | 7 (5) | 0 | 8 (6) | 63 |
| Dulaglutide 0.75 mg (s.c.) | 53 (82) | 0 | 6 (9) | 1 (2) | 4 (6) | 0 | 0 | 1 (2) | 0 | 3 (5) | 0 | 2 (3) | 50 |
| SUSTAIN 1 | |||||||||||||
| S.c. semaglutide 0.5 mg | 82 (64) | 0 | 26 (20) | 5 (4) | 16 (13) | 0 | 0 | 3 (2) | 0 | NR | 0 | 8 (6) | 63 |
| S.c. semaglutide 1 mg | 73 (56) | 0 | 31 (24) | 9 (7) | 14 (11) | 0 | 0 | 1 (<1) | 0 | NR | 0 | 7 (5) | 57 |
| Placebo | 69 (53) | 3 (2) | 10 (8) | 2 (2) | 3 (2) | 0 | 0 | 0 | 0 | NR | 0 | 3 (2) | 33 |
| SUSTAIN 2 | |||||||||||||
| S.c. semaglutide 0.5 mg | 306 (75) | 7 (2) | 73 (18) | 33 (8) | 54 (13) | 3 (1%) | NR | 1 (<1) | 0 | 1 (<1) | NR | 33 (8) | 82 |
| S.c. semaglutide 1 mg | 292 (71) | 2 (<1) | 72 (18) | 41 (10) | 53 (13) | 1 (<1) | NR | 7 (2) | 1 | 0 | NR | 39 (10) | 79 |
| Sitagliptin 100 | 292 (72) | 5 (1) | 30 (7) | 11 (3) | 29 (7) | 0 | NR | 6 (1) | 0 | 3 (1) | NR | 12 (3) | 25 |
| SUSTAIN 3 | |||||||||||||
| S.c. semaglutide 1 mg | 303 (75) | 33 (8.2) | 90 (22.3) | 29 (7.2) | 46 (11.4) | 2 (<1) | NR | 6 (1%) | NR | NR | NR | 38 (9.4) | NR |
| Exenatide ER 2.0 mg | 309 (76.3) | 33 (8.1) | 48 (11.9) | 25 (6.2) | 34 (8.4) | 3 (<1) | NR | 2 (<1) | NR | NR | NR | 29 (7.2) | NR |
| SUSTAIN 4 | |||||||||||||
| S.c. semaglutide 0.5 mg | 253 (70) | 16 (4) | 77 (21) | 24 (7) | 59 (16) | 2 (1) | 1 (<1) | 1 (<1) | NR | 1 (<1) | NR | 20 (6) | 55 |
| S.c. semaglutide 1 mg | 264 (73) | 20 (6) | 80 (22) | 37 (10) | 69 (19) | 0 | 0 | 2 (1) | NR | 0 | NR | 27 (8) | 70 |
| Insulin glargine | 235 (65) | 38 (11) | 13 (4) | 11 (3) | 16 (4) | 0 | 0 | 0 | NR | 1 (<1) | NR | 4 (1) | 0 |
| SUSTAIN 5 | |||||||||||||
| S.c. semaglutide 0.5 mg | 91 (68.9) | 11 (8.3) | 15 (11.4) | 8 (6.1) | 6 (4.5) | 0 | 0 | 3 (2.3) | 0 | (3.0) | NR | 6 (4.5) | NR |
| S.c. semaglutide 1 mg | 84 (64.1) | 14 (10.7) | 22 (16.8) | 15 (11.5) | 9 (6.9) | 0 | 0 | 1 (0.8) | 0 | (0.8) | NR | 8 (6.1) | NR |
| Placebo | 77 (57.9) | 7 (5.3) | 6 (4.5) | 4 (3.0) | 2 (1.5) | 0 | 0 | 0 | 0 | 0 | NR | 1 (0.8) | NR |
| SUSTAIN 6 | |||||||||||||
| S.c. semaglutide 0.5 mg | 740 (89.6) | 191 (23.1) | 143 (17.3) | 14 (1.7) | 15 (1.8) | 6 (0.7) | 0 | 25 (3) | 0 | 42 (5.1) | 95 (11.5) | 49 | |
| S.c. semaglutide 1 mg | 732 (89.1) | 178 (21.7) | 180 (21.9) | 23 (2.8) | 19 (2.3) | 3 (0.4) | 1 (0.1) | 17 (2.1) | 0 | 50 (3.0) | 23 (2.8) | 119 (14.5) | 65 |
| Placebo | 1484 (90) | 350 (21.2) | 129 (7.8) | 5 (0.3) | 7 (0.4) | 12 (0.7) | 4 (0.2) | 39 (2.3) | 0 | 29 (1.8) | 34 (4.1) | 110 (6.7) | 16 |
| SUSTAIN 7 | |||||||||||||
| S.c. semaglutide 0.5 mg | 204 (68) | 2 (1) | 68 (23) | 31 (10) | 43 (14) | 0 | 0 | 2 (1) | 1 (<1) | 2 (1) | NR | 24 (8) | 67 |
| S.c. semaglutide 1 mg | 207 (69) | 5 (2) | 63 (21) | 31 (10) | 41 (14) | 0 | 0 | 4 (1) | 0 | 2 (1) | NR | 29 (10) | 62 |
| Dulaglutide 0.75 mg (s.c.) | 186 (62) | 3 (1) | 39 (13) | 12 (4) | 23 (8) | 0 | 0 | 4 (1) | 0 | 2 (1) | NR | 14 (5) | 43 |
| Dulaglutide 1.5 mg (s.c.) | 221 (74) | 5 (2) | 60 (20) | 29 (10) | 53 (18) | 0 | 0 | 8 (3) | 1 (<1) | 3 (1) | NR | 20 (7) | 70 |
| SUSTAIN 8 | |||||||||||||
| S.c. semaglutide 1 mg | 298 (76) | 53 (14) | 89 (23) | 50 (13) | 60 (15) | NR | NR | NR | NR | 9 (2) | 4 (1) | 38 (10) | 68 |
| Canagliflozin 300 mg | 283 (72) | 32 (8) | 26 (7) | 9 (2) | 37 (9) | NR | NR | NR | NR | 15 (4) | 0 | 20 (5) | 20 |
| SUSTAIN 9 | |||||||||||||
| S.c. semaglutide 1 mg | 104 (69.3) | 17 (11.3) | 29 (19.3) | 14 (9.3) | 17 (11.3) | 0 | 0 | NR | NR | 3 (2.0) | 1 (0.7) | 13 (8.7) | 77 |
| Placebo | 91 (60.3) | 3 (2.0) | 5 (3.3) | 3 (2.0) | 9 (6.0) | 0 | 0 | NR | NR | 8 (5.3) | 0 | 3 (2.0) | 0 |
| SUSTAIN 10 | |||||||||||||
| S.c. semaglutide 1 mg | 204 (70.6) | 5 (1.7) | 63 (21.8) | 30 (10.4) | 45 (15.6) | 0 | NR | NR | NR | 3 (1.0) | NR | 33 (11.4) | 67 |
| Liraglutide 1.2 mg (s.c.) | 190 (66.2) | 7 (2.4) | 45 (15.7) | 23 (8.0) | 35 (12.2) | 2 (0.7%) | NR | NR | NR | 4 (1.4) | NR | 19 (6.6) | 58 |
| SUSTAIN JAPAN 'SITA' | |||||||||||||
| S.c. semaglutide 0.5 mg | 77 (74.8) | 0 | (10.7) | (6.8%) | 0 | 0 | 1 (1.0) | 0 | 4 (3.9) | NR | 3 (2.9) | NR | |
| S.c. semaglutide 1 mg | 73 (71.6) | 1 (1.0) | (12.7) | (8.8%) | 0 | 0 | 3 (2.9) | 0 | 2 (1.9) | NR | 11 (10.8) | NR | |
| Sitagliptin 100 mg | 68 (66.0) | 0 | 0 | (1.9%) | 0 | 1 (1.0) | 0 | 0 | 4 (3.9) | NR | 2 (1.9) | NR | |
| SUSTAIN JAPAN 'INDIVIDUAL' | |||||||||||||
| S.c. semaglutide 0.5 mg | 206 (86.2) | 3 (1.3) | 29 (12.1) | 13 (5.4) | 24 (10.0) | 0 | 0 | 4 (1.7%) | 0 | 11 (4.6) | NR | 14 (5.9) | NR |
| S.c. semaglutide 1 mg | 212 (88) | 6 (2.5) | 46 (19.1) | 14 (5.8) | 38 (15.8) | 0 | 0 | 2 (0.8%) | 0 | 16 (6.6) | NR | 26 (10.8) | NR |
| Additional OAD (investigators discretion) | 86 (71.7) | 2 (1.7) | 1 (0.8) | 2 (1.7) | 8 (6.7) | 0 | 0 | 0 | 0 | 6 (5.0) | NR | 4 (3.3) | NR |
| SUSTAIN China | |||||||||||||
| S.c. semaglutide 0.5 mg | 209 (72.8%) | 2 (0.7%) | 22 (7.7%) | 14 (4.9%) | 58 (20.2%) | 0 | 0 | NR | NR | 19 (6.6%) | NR | 17 (5.9%) | 59 |
| S.c. semaglutide 1 mg | 216 (74,5%) | 6 (2.1%) | 39 (13.4%) | 19 (6.6%) | 49 (16.9%) | 1 (0.3%) | 0 | NR | NR | 14 (4.8%) | NR | 31 (10.7%) | 68 |
| Sitagliptin 100 mg | 199 (68,6%) | 4 (1.4%) | 5 (1.7%) | 3 (1.0%) | 20 (6.9%) | 0 | 0 | NR | NR | 10 (3.4%) | NR | 6 (2.1%) | 17 |
AE, adverse event; ER, extended release; NR, not reported; OAD, oral antidiabetic drug; s.c. subcutaneous.
An independent external adjudication committee (EAC) validated prespecified categories of adverse events (including deaths, selected cardiovascular events, malignant neoplasms, thyroid diseases [malignant thyroid neoplasms and C-cell hyperplasia], acute kidney injury, acute pancreatitis, and lactic acidosis) except in SUSTAIN 10 where there was no adjudication.
*An episode that was severe according to the ADA classification (requires assistance of another person to actively administer carbohydrate, glucagon, or other corrective action) or an episode with confirmed blood glucose value <56 mg/dL and symptoms consistent with hypoglycemia.