A summary of the PIONEER 4 trial: Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes

A summary of the PIONEER 4 trial: Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes

Analisa Buysse, PharmD, Avera Marshall Regional Medical Center

Background: Glucagon-like peptide-1 (GLP-1) agonists have become commonplace in the treatment of type 2 diabetes. In addition to effectively lowering HbA1c, agents in the GLP-1 agonist class also provide cardiovascular benefit – namely, liraglutide (Victoza®) and semaglutide (Ozempic®). However, many patients hesitate to initiate therapy with these agents because they do not desire to use injectable medications. An oral formulation of the GLP-1 agonist, semaglutide may soon change this landscape as it has yielded promising results in previous phase 2 and phase 3 trials.

Purpose: The objective of the PIONEER 4 trial was to compare the efficacy and safety of oral semaglutide with subcutaneous liraglutide and placebo in patients with type 2 diabetes currently taking metformin with or without a sodium-glucose cotransporter-2 inhibitor.

Study Design: The PIONEER 4 trial was a randomized, multi-center, 52 week, double-blind, double-dummy, active-controlled, and placebo-controlled phase 3a study. The primary outcome was the change in HbA1c from baseline to 26 weeks. A notable secondary endpoint included the change in body weight from baseline to week 26. Results were assessed using both intention-to-treat and per-protocol principles and analyzed using ANCOVA and a mixed model for continuous endpoints, respectively. Power was set at 90% to confirm the superiority of semaglutide to placebo and the non-inferiority of oral semaglutide to liraglutide using a non-inferiority margin of 0.4%. Alpha was set at 0.05.

Patients were randomized in a 2:2:1 ratio to receive oral semaglutide (initiated at a once-daily dose of 3mg, which was then titrated to 7mg after four weeks and 14mg after eight weeks), subcutaneous liraglutide (initiated at 0.6mg daily, titrated to 1.2mg after one week and 1.8mg after two weeks), or placebo. Patients were informed to take the oral study drug with up to half a glass of water in a fasted state every morning, at least 30 minutes prior to their first meal.

Results: After 26 weeks, the average change from baseline in HbA1c was -1.2% for oral semaglutide, -1.1% for liraglutide, and -0.2% for placebo when analyzed using the intention-to-treat principle. Authors asserted based on these data that oral semaglutide was non-inferior to subcutaneous liraglutide [estimated treatment difference (ETD) -0.1%, 95% CI -0.3 to 0.0; P<0.0001 for non-inferiority] and superior to placebo [ETD -1.1%, 95% CI -1.2 to -0.9; P<0.0001]. When analyzed using the per-protocol principle, oral semaglutide decreased the HbA1c more than both subcutaneous liraglutide [ETD -0.2%, 95% CI -0.3 to -0.1; P=0.0056] and placebo [ETD -1.2%, 95% CI -1.4 to -1.0; P<0.0001].

Notably, patients randomized to oral semaglutide lost more weight by week 26 than patients receiving liraglutide [-4.4 kg vs -3.1 kg, ETD -1.2 kg, 95% CI -1.9 to -0.6; P=0.0003] and placebo [ETD -3.8 kg, 95% CI -4.7 to -3.0; P<0.0001] when assessed using an intention-to-treat analysis.

Side effects were reported by 80% (229/285) of patients treated with semaglutide, 74% (211/284) treated with liraglutide, and 67% (95/142) receiving placebo. Authors stated that the higher incidence of adverse effects in the semaglutide group was largely due to gastrointestinal side effects, such as transient nausea and diarrhea.

Conclusions: Overall, oral semaglutide offers a promising future oral alternative for patients with type 2 diabetes who would benefit from GLP-1 agonist therapy but refuse injections. The adverse effect profile of oral semaglutide appears similar to subcutaneous GLP-1 agonists, although may cause additional gastrointestinal side effects based on the results of this study. Further studies would be necessary to prove the presence of cardiovascular benefit with oral semaglutide as has been documented with injectable GLP-1 agonists.

Key Point: An oral GLP-1 agonist option is likely on the horizon for type 2 diabetes treatment.


1. Pratley R, Amod A, Tetens-Hoff S, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019;394:39-50.