Table 4.
Incidence of select adverse events (on-treatment) of interest during treatment in phase III clinical trials
| Overall AE incidence | Incidence of select GI AEsa | Premature trial product discontinuation | Hypoglycemia | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any AE n (%) |
Serious AEs n (%) |
Nausea n (%) |
Diarrhea n (%) |
Vomiting n (%) |
Due to any AE n (%) |
Due to GI AE n (%) |
Severeb or BG-confirmed symptomatic episodec n (%) |
Severe episodeb n (%) |
||||
| Active-controlled trials | ||||||||||||
|
PIONEER 2 [47] Patient population: T2D; background therapy: metformin; duration: 52 weeks |
Oral semaglutide 14 mg (n = 410) | 289 (70) | 27 (7) | 81 (20) | 38 (9) | 30 (7) | 44 (11) | 33 (8) | 7 (2) | 1 (0) | ||
| Empagliflozin 25 mg (n = 409) | 283 (69) | 37 (9) | 10 (2) | 13 (3) | 7 (2) | 18 (4) | 3 (1) | 8 (2) | 1 (0) | |||
|
PIONEER 3 [48] Patient population: T2D; background therapy: metformin ± SU; duration: 78 weeks |
Oral semaglutide 3 mg (n = 466) | 370 (79) | 64 (14) | 34 (7) | 45 (10) | 13 (3) | 26 (6) | 11 (2) | 23 (5) | 0 (0) | ||
| Oral semaglutide 7 mg (n = 464) | 363 (78) | 47 (10) | 62 (13) | 53 (11) | 28 (6) | 27 (6) | 16 (3) | 24 (5) | 0 (0) | |||
| Oral semaglutide 14 mg (n = 465) | 370 (80) | 44 (9) | 70 (15) | 57 (12) | 42 (9) | 54 (12) | 32 (7) | 36 (8) | 1 (0) | |||
| Sitagliptin 100 mg (n = 466) | 388 (83) | 58 (12) | 32 (7) | 37 (8) | 19 (4) | 24 (5) | 12 (3) | 39 (8) | 4 (1) | |||
|
PIONEER 7 [52] Patient population: T2D; background therapy: 1–2 oral glucose-lowering drugsd; duration: 52 weeks |
Oral semaglutide with flexible dose adjustmente (n = 253) | 197 (78) | 24 (9) | 53 (21) | 22 (9) | 14 (6) | 22 (9) | 14 (6) | 14 (6) | 0 (0) | ||
| Sitagliptin 100 mg (n = 250) | 172 (69) | 24 (10) | 6 (2) | 8 (3) | 2 (1) | 8 (3) | 2 (1) | 14 (6) | 0 (0) | |||
|
PIONEER 10 [55] Patient population: Japanese patients with T2D; background therapy: one oral glucose-lowering drugsf; duration: 52 weeks |
Oral semaglutide 3 mg (n = 131) | 101 (77) | 9 (7) | 7 (5) | 2 (2) | 3 (2) | 4 (3) | 2 (2) | 3 (2) | 0 (0) | ||
| Oral semaglutide 7 mg (n = 132) | 106 (80) | 4 (3) | 11 (8) | 2 (2) | 1 (1) | 8 (6) | 4 (3) | 3 (2) | 0 (0) | |||
| Oral semaglutide 14 mg (n = 130) | 111 (85) | 7 (5) | 12 (9) | 10 (8) | 9 (7) | 8 (6) | 5 (4) | 4 (3) | 0 (0) | |||
| Dulaglutide 0.75 mg (n = 65) | 53 (82) | 1 (2) | 6 (9) | 4 (6) | 1 (2) | 2 (3) | 1 (2) | 0 (0) | 0 (0) | |||
| Active- and placebo-controlled trials | ||||||||||||
|
PIONEER 9 [54] Patient population: Japanese patients with T2D background therapy: diet and exercise; duration: 52 weeks |
Oral semaglutide 3 mg (n = 49) | 37 (76) | 2 (4) | 2 (4) | 4 (8) | NR | 1 (2) | 1 (2) | 0 (0) | 0 (0) | ||
| Oral semaglutide 7 mg (n = 49) | 37 (76) | 3 (6) | 5 (10) | 1 (2) | NR | 1 (2) | 1 (2) | 0 (0) | 0 (0) | |||
| Oral semaglutide 14 mg (n = 48) | 34 (71) | 0 (0) | 4 (8) | 3 (6) | NR | 2 (4) | 1 (2) | 0 (0) | 0 (0) | |||
| Liraglutide 0.9 mg (n = 48) | 32 (67) | 0 (0) | 0 (0) | 2 (4) | NR | 0 (0) | 0 (0) | 2 (4) | 0 (0) | |||
| Placebo (n = 49) | 39 (80) | 3 (6) | 1 (2) | 1 (2) | NR | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |||
|
PIONEER 4 [49] Patient population: T2D; background therapy: metformin ± SGLT2i; duration: 52 weeks |
Oral semaglutide 14 mg (n = 285) | 229 (80) | 31 (11) | 56 (20) | 43 (15) | 25 (9) | 31 (11) | 22 (8) | 2 (1) | NR | ||
| Liraglutide 1.8 mg (n = 284) | 211 (74) | 22 (8) | 51 (18) | 31 (11) | 13 (5) | 26 (9) | 17 (6) | 7 (2) | NR | |||
| Placebo (n = 142) | 95 (67) | 15 (11) | 5 (4) | 11 (8) | 3 (2) | 5 (4) | 3 (2) | 3 (2) | NR | |||
| Placebo-controlled trials | ||||||||||||
|
PIONEER 8 [53] Patient population: T2D; background therapy: insulin ± metformin; duration: 52 weeks |
Oral semaglutide 3 mg (n = 184) | 137 (74) | 25 (14) | 21 (11) | 16 (9) | 11 (6) | 13 (7) | 9 (5) | 52 (28) | 5 (3) | ||
| Oral semaglutide 7 mg (n = 181) | 142 (78) | 19 (10) | 30 (17) | 22 (12) | 14 (8) | 16 (9) | 12 (7) | 47 (26) | 1 (1) | |||
| Oral semaglutide 14 mg (n = 181) | 151 (83) | 12 (7) | 42 (23) | 27 (15) | 18 (10) | 24 (13) | 19 (10) | 48 (27) | 2 (1) | |||
| Placebo (n = 184) | 139 (76) | 17 (9) | 13 (7) | 11 (6) | 7 (4) | 5 (3) | 1 (1) | 54 (29) | 1 (1) | |||
|
PIONEER 1 [46] Patient population: T2D; background therapy: diet and exercise alone; duration: 52 weeks |
Oral semaglutide 3 mg (n = 175) | 101 (58) | 5 (3) | 14 (8) | 15 (9) | 5 (3) | 4 (2) | 3 (2) | 5 (3) | 0 (0) | ||
| Oral semaglutide 7 mg (n = 175) | 93 (53) | 3 (2) | 9 (5) | 9 (5) | 8 (5) | 7 (4) | 4 (2) | 2 (1) | 1 (1) | |||
| Oral semaglutide 14 mg (n = 175) | 99 (57) | 2 (1) | 28 (16) | 9 (5) | 12 (7) | 13 (7) | 9 (5) | 1 (1) | 0 (0) | |||
| Placebo (n = 178) | 99 (56) | 8 (4) | 10 (6) | 4 (2) | 4 (2) | 4 (2) | 1 (1) | 1 (1) | 0 (0) | |||
|
PIONEER 5 [50] Patient population: T2D with moderate renal impairmentg; background therapy: metformin, SU or metformin + SU, or basal insulin ± metformin; duration: 26 weeks |
Oral semaglutide 14 mg (n = 163) | 122 (75) | 17 (10) | 31 (19) | 17 (10) | 19 (12) | 24 (15) | 19 (12) | 9 (6) | 0 (0) | ||
| Placebo (n = 161) | 109 (68) | 17 (11) | 12 (7) | 6 (4) | 2 (1) | 8 (5) | 3 (2) | 3 (2) | 0 (0) | |||
|
PIONEER 6 [51] Patient population: T2D at high CV riskh; background therapy: standard of care; duration: Event driven. Median follow-up of 16 months |
Oral semaglutide 14 mg (n = 1591) | NR | 301 (19) | NR | NR | NR | 184 (12) | 108 (7) | NR | 23 (1) | ||
| Placebo (n = 1592) | NR | 358 (22) | NR | NR | NR | 104 (7) | 26 (2) | NR | 13 (1) | |||
All data are number of patients (% of patients); percentages have been rounded to the nearest whole number
All study drugs were given once daily
AE adverse event, BG blood glucose, CV cardiovascular, GI gastrointestinal, HbA1c glycated hemoglobin, NR not reported, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes, TZD thiazolidinedione
aGI events were only reported if occurring in > 5% of patients in any group
bSevere hypoglycemia defined as per American Diabetes Association classification (requiring assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions) [92], except for PIONEER 6, in which severe hypoglycemia was identified through a search of Medical Dictionary for Regulatory Activities terms (version 20.1)
cConfirmed based on BG < 56 mg/dL (< 3.1 mmol/L) with symptoms consistent with hypoglycemia
dIncluding metformin, SU, SGLT2i, or TZD
eOral semaglutide was initiated at 3 mg once daily; dose adjustment was performed every 8 weeks, with doses increased (to 7 mg and then 14 mg) if HbA1c was ≥7.0% (≥53 mmol/mol), maintained if HbA1c was < 7.0% (< 53 mmol/mol), and reduced (minimum dose of 3 mg) if moderate-to-severe nausea or vomiting was reported in the 3 days within the week prior to the dose-adjustment assessment (regardless of HbA1c level)
fIncluding SU, glinide, TZD, alpha-glucosidase inhibitor, or SGLT2i
gEstimated glomerular filtration rate 30–59 mL/min/1.73 m2
hPatients were eligible if they were 50 years or older and had established CV disease or chronic kidney disease, or 60 years or older and had CV risk factors