Table 3.
Efficacy of oral semaglutide in patients with T2D, summary of observations from key supportive secondary endpoints in the phase III clinical trials
| Trial | Time point | Treatment (no. of patients) | Endpoint | ||
|---|---|---|---|---|---|
| % achieving HbA1c < 7% (53 mmol/mol) | % achieving composite HbA1c < 7% (53 mmol/mol) without hypoglycemiaa and no weight gain | Estimated mean change from baseline SBP (mmHg) (on-treatment period) | |||
| Active-comparator trials | |||||
|
PIONEER 2 [47] Population and background therapy: patients with T2D on metformin |
Week 26 | Oral semaglutide 14 mg (n = 411) | 66.8††† | 60.5††† | − 5 |
| Empagliflozin 25 mg (n = 410) | 40.0 | 35.7 | − 5 | ||
| Week 52 | Oral semaglutide 14 mg (n = 411) | 66.1††† | 55.7††† | − 5 | |
| Empagliflozin 25 mg (n = 410) | 43.2 | 39.0 | − 4 | ||
|
PIONEER 3 [48] Population and background therapy: patients with T2D on metformin ± SU |
Week 26 | Oral semaglutide 3 mg (n = 466) | 27 | 20 | − 1 |
| Oral semaglutide 7 mg (n = 465) | 42††† | 34††† | − 3 | ||
| Oral semaglutide 14 mg (n = 465) | 55††† | 46††† | − 3 | ||
| Sitagliptin 100 mg (n = 467) | 32 | 20 | − 2 | ||
| Week 52 | Oral semaglutide 3 mg (n = 466) | 27 | 20 | − 2 | |
| Oral semaglutide 7 mg (n = 465) | 38† | 30††† | − 4††† | ||
| Oral semaglutide 14 mg (n = 465) | 53††† | 43††† | − 3†† | ||
| Sitagliptin 100 mg (n = 467) | 31 | 20 | − 1 | ||
| Week 78 | Oral semaglutide 3 mg (n = 466) | 27 | 20 | − 2 | |
| Oral semaglutide 7 mg (n = 465) | 37† | 31††† | − 3†† | ||
| Oral semaglutide 14 mg (n = 465) | 44††† | 34††† | − 3† | ||
| Sitagliptin 100 mg (n = 467) | 29 | 19 | 0 | ||
|
PIONEER 7b [52] Population and background therapy: patients with T2D on 1–2 oral glucose-lowering drugsc |
Week 52 | Oral semaglutide flexible dose (n = 253) | 58††† | 45††† | − 4 |
| Sitagliptin 100 mg (n = 251) | 25 | 15 | − 2 | ||
|
PIONEER 10 [55] Population and background therapy: Japanese patients with T2D on one oral glucose-lowering drugd |
Week 26 | Oral semaglutide 3 mg (n = 131) | 46§§§ | 30 | − 3 |
| Oral semaglutide 7 mg (n = 132) | 75 | 49 | − 5 | ||
| Oral semaglutide 14 mg (n = 130) | 82† | 66††† | − 6 | ||
| Dulaglutide 0.75 mg (n = 65) | 70 | 39 | − 3 | ||
| Week 52 | Oral semaglutide 3 mg (n = 131) | 34§§ | 18 | − 2 | |
| Oral semaglutide 7 mg (n = 132) | 60 | 41† | − 2 | ||
| Oral semaglutide 14 mg (n = 130) | 71†† | 56††† | − 2 | ||
| Dulaglutide 0.75 mg (n = 65) | 51 | 25 | − 1 | ||
| Active- and placebo-controlled trials | |||||
|
PIONEER 9 [54] Population and background therapy: Japanese patients with T2D on diet and exercise |
Week 26 | Oral semaglutide 3 mg (n = 49) | 52*** | 33** | − 3 |
| Oral semaglutide 7 mg (n = 49) | 69*** | 53*** | − 4 | ||
| Oral semaglutide 14 mg (n = 48) | 81***† | 70***†† | − 2 | ||
| Liraglutide 0.9 mg (n = 48) | 53 | 33 | − 1 | ||
| Placebo (n = 49) | 16 | 8 | − 4 | ||
| Week 52 | Oral semaglutide 3 mg (n = 49) | 43** | 28* | − 1 | |
| Oral semaglutide 7 mg (n = 49) | 63*** | 53***†† | − 1 | ||
| Oral semaglutide 14 mg (n = 48) | 72*** | 62***†† | − 2 | ||
| Liraglutide 0.9 mg (n = 48) | 49 | 24 | 1 | ||
| Placebo (n = 49) | 14 | 8 | − 3 | ||
|
PIONEER 4 [49] Population and background therapy: patients with T2D on metformin ± SGLT2i |
Week 26 | Oral semaglutide 14 mg (n = 285) | 68*** | 61*** | − 4 |
| Liraglutide 1.8 mg (n = 284) | 62 | 54 | − 4 | ||
| Placebo (n = 142) | 14 | 11 | − 2 | ||
| Week 52 | Oral semaglutide 14 mg (n = 285) | 61*** | 56*** | − 3* | |
| Liraglutide 1.8 mg (n = 284) | 55 | 48 | − 3 | ||
| Placebo (n = 142) | 15 | 11 | − 0 | ||
| Placebo-controlled trials | |||||
|
PIONEER 8 [53] Population and background therapy: patients with T2D on insulin ± metformin |
Week 26 | Oral semaglutide 3 mg (n = 184) | 28*** | 18*** | − 2 |
| Oral semaglutide 7 mg (n = 182) | 43*** | 27*** | − 3** | ||
| Oral semaglutide 14 mg (n = 181) | 58*** | 44*** | − 4*** | ||
| Placebo (n = 184) | 7 | 2 | 1 | ||
| Week 52 | Oral semaglutide 3 mg (n = 184) | 29*** | 16** | − 1 | |
| Oral semaglutide 7 mg (n = 182) | 40*** | 25*** | − 2 | ||
| Oral semaglutide 14 mg (n = 181) | 54*** | 36*** | − 5*** | ||
| Placebo (n = 184) | 9 | 5 | − 0 | ||
|
PIONEER 1 [46] Population and background therapy: patients with T2D on diet and exercise |
Week 26 | Oral semaglutide 3 mg (n = 175) | 55*** | 37** | − 4 |
| Oral semaglutide 7 mg (n = 175) | 69*** | 57*** | − 4 | ||
| Oral semaglutide 14 mg (n = 175) | 77*** | 69*** | − 5 | ||
| Placebo (n = 178) | 31 | 23 | − 2 | ||
|
PIONEER 5 [50] Population and background therapy: patients with T2D and moderate renal impairmente on metformin ± SU, SU alone, or basal insulin ± metformin |
Week 26 | Oral semaglutide 14 mg (n = 163) | 58*** | 51*** | − 7*** |
| Placebo (n = 161) | 23 | 17 | − 0 | ||
All data presented are for the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Data have been rounded to the nearest whole number. Systolic blood pressure data expressed are on-treatment
For patients achieving HbA1c or composite targets, observed proportions are given except for PIONEER 3 (where estimated proportions were reported) and p values are for the odds of achieving target
HbA1c glycated hemoglobin, SBP systolic blood pressure, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes, TZD thiazolidinedione
*p < 0.05, **p < 0.01, ***p < 0.001 favoring oral semaglutide vs. placebo
†p < 0.05, ††p < 0.01, †††p < 0.001 favoring oral semaglutide vs. active comparator
§p < 0.05, §§p < 0.01, §§§p < 0.001 favoring active comparator vs. oral semaglutide
aSevere hypoglycemia (based on the American Diabetes Association classification) or confirmed hypoglycemia based on blood glucose <56 mg/dL (< 3.1 mmol/L) with symptoms consistent with hypoglycemia
bOral 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). Achievement of HbA1c < 7% (53 mmol/mol) was the primary endpoint in this study
cIncluding metformin, SU, SGLT2i, or TZD
dIncluding SU, glinide, TZD, alpha-glucosidase inhibitor, or SGLT2i
eEstimated glomerular filtration rate 30–59 mL/min/1.73 m2