Introduction: A post hoc analysis of the PIONEER 1–5 and 8 trials assessed the clinically relevant composite endpoints of HbA_1c (glycated haemoglobin) reduction ≥ 1% and body weight loss of ≥ 5% or ≥ 10% with orally administered semaglutide versus comparators. Methods: In the PIONEER trials, people with type 2 diabetes were randomised to orally administered semaglutide versus placebo (PIONEER 1, 4, 5 and 8), empagliflozin (PIONEER 2), sitagliptin (PIONEER 3) and liraglutide (PIONEER 4) for 26–78 weeks. This analysis assessed the proportion of people achieving an HbA_1c reduction of ≥ 1% and body weight loss of ≥ 5% at week 26 and at end of treatment, and the proportion of people achieving an HbA_1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment. Results: Overall, 3506 people in PIONEER 1–5 and 8 were included. At week 26 and at end of treatment, odds of achieving the composite endpoint of an HbA_1c reduction of ≥ 1% and body weight loss of ≥ 5% were significantly greater with orally administered semaglutide 14 mg than with placebo (PIONEER 1, 4, 5 and 8; all p < 0.0001), empagliflozin 25 mg (PIONEER 2, p < 0.0001), sitagliptin 100 mg (PIONEER 3, p < 0.0001) and liraglutide 1.8 mg (PIONEER 4, p < 0.0001). Odds of achieving the composite endpoint of HbA_1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment were also significantly greater with orally administered semaglutide versus comparators. Conclusion: In PIONEER 1–5 and 8, odds of achieving clinically relevant reductions in both HbA_1c and body weight were significantly greater with orally administered semaglutide versus comparators. Graphical Abstract: [Figure not available: see fulltext.]