Table 1.

Summary of result from the global PIONEER trials

Trial	Intervention	Comparator	Population	Primary endpoint(s)a		Secondary endpoint(s)a		Results summary
PIONEER 1 (Aroda et al. [26])	Semaglutide (3, 7 or 14 mg); monotherapy	Placebo	HbA1c 7.0–9.5%; management by diet and exercise (n = 703)	HbA1c change (%), week 26	ETD: 3 mg: − 0.6%* 7 mg: − 0.9%* 14 mg: − 1.1%*	Body weight change, week 26	ETD: 3 mg: − 0.1 kg 7 mg: − 0.9 kg 14 mg: − 2.3 kg*	Semaglutide (7 mg, 14 mg) resulted in significant reductions in HbA1c and body weight
PIONEER 2 (Rodbard et al. [14])	Semaglutide (14 mg) + metformin	Empagliflozin (25 mg) + metformin	HbA1c 7.0–10.5%; uncontrolled on metformin (n = 787)	HbA1c change (%), week 26	− 1.3 vs. − 0.9%*	Body weight change, week 26	− 3.8 vs. − 3.7 kg	Semaglutide was superior to empagliflozin with meaningful reductions in HbA1c at 26 weeks Superior weight loss not confirmed at week 26, significantly better than empagliflozin at week 52
PIONEER 3 (Rosenstock et al. [15])	Semaglutide (3, 7, or 14 mg) + metformin ± SU	Sitagliptin (100 mg) + metformin ± SU	HbA1c 7.0–10.5%; uncontrolled on metformin (n = 1864)	HbA1c change (%), week 26	ETD: 3 mg:  + 0.13% 7 mg: − 0.3%* 14 mg: − 0.5%*	Body weight change, week 26	ETD: 3 mg: − 0.6 kg 7 mg: − 1.6 kg* 14 mg: − 2.5 kg*	Semaglutide (7 mg, 14 mg) resulted in significantly greater reductions in HbA1c and body weight
PIONEER 4 (Pratley et al. [13])	Semaglutide (14 mg) + metformin ± SGLT2 inhibitor	Liraglutide (1.8 mg) + metformin ± SGLT2 inhibitor Placebo + metformin ± SGLT2 inhibitor	HbA1c 7.0–9.5%; uncontrolled on metformin (n = 711)	HbA1c change (%), week 26	− 1·2 vs. − 1.1* vs. −  0.2%*	Body weight change, week 26	− 4.4 vs. − 3.1 vs. − 0.5 kg*	Semaglutide was non-inferior to daily injections of liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight over both comparators at week 26
PIONEER 5 (Mosenzon et al. [28])	Semaglutide (14 mg) ± metformin ± SU; semaglutide (14 mg) ± basal insulin ± metformin	Placebo ± metformin ± SU Placebo ± basal insulin ± metformin	HbA1c 7.0–9.5%; eGFR 30–59 mL/min per 1.73 m2 (n = 324)	HbA1c change (%), week 26	− 1.0 vs. − 0.2%*	Body weight change, week 26	− 3.4 vs. − 0.9 kg*	Semaglutide (14 mg) was superior to placebo in decreasing HbA1c and bodyweight
PIONEER 6 (Husain et al. [27])	Semaglutide (target dose: 14 mg)	Placebo	Age ≥ 50 years, established CV/CKD Age ≥ 60 years, CV risk factors only (n = 3183)	First occurrence of a MACE	3.8 vs. 4.8% HR: 0.79*	MACE + unstable angina or hHF	5.2 vs. 6.3% HR: 0.82	Noninferiority of oral semaglutide to placebo, ruling out an 80% excess cardiovascular risk
PIONEER 7 (Pieber et al. [29])	Semaglutide (flexible dose adjustment: 3, 7, or 14 mg) + metformin, SGLT2 inhibitor, SU or thiazolidinediones	Sitagliptin (100 mg) + metformin, SGLT2 inhibitor, SU or thiazolidinediones	HbA1c 7.5–9.5% (n = 504)	HbA1c change (< 7%), week 52	58 vs. 25% OR: 4.40*	Body weight change, week 52	− 2.6 vs. − 0.7 kg*	Semaglutide provided superior glycaemic control and weight loss compared with sitagliptin
PIONEER 8 (Zinman et al. [30])	Semaglutide (3, 7 or 14 mg) + insulin ± metformin	Placebo + insulin ± metformin	HbA1c 7.0–9.5% (n = 731)	HbA1c change (%), week 26	ETD: 3 mg: − 0.5%* 7 mg: − 0.9%* 14 mg: − 1.2%*	Body weight change, week 52	ETD: 3 mg: − 0.9 kg 7 mg: − 2.0 kg* 14 mg: − 3.3 kg*	Semaglutide was superior to placebo in reducing HbA1c and body weight

ACM all-cause mortality, CKD chronic kidney disease, CV cardiovascular, eGFR estimated glomerular rate ETD estimated treatment difference, HbA1c haemoglobin A1c, hHF hospitalisation for heart failure, HR hazard ratio, MACE major adverse cardiovascular event, MI myocardial infarction, OR odds ratio, SGLT2 sodium-glucose cotransporter-2, SU sulfonylurea

*Statistically significant result

^aEfficacy assessed according to the treatment policy estimand, defined as the difference between treatments in change in HbA1c and body weight regardless of trial product discontinuation and/or addition of rescue medication