ArticlesOral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial
Introduction
Glucagon-like peptide-1 (GLP-1) receptor agonists that are currently available for the treatment of type 2 diabetes are all administered by subcutaneous injection.1 Within the class, substantial differences in structure, dosing interval, and efficacy exist. Liraglutide is a once-daily GLP-1 receptor agonist that decreases glycated haemoglobin (HbA1c) and bodyweight in patients with type 2 diabetes across the continuum of care.2, 3 Among once-weekly GLP-1 receptor agonists, subcutaneous semaglutide has superior glycaemic control and weight loss compared with exenatide and dulaglutide.4, 5 Both liraglutide and subcutaneous semaglutide have shown a cardiovascular benefit and are recommended for patients with type 2 diabetes and cardiovascular disease.6, 7, 8
An oral formulation of semaglutide is in development. Orally delivered peptides typically have low bioavailability and so oral semaglutide is co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which facilitates semaglutide absorption across the gastric mucosa.9 In previous trials, oral semaglutide showed significantly greater decreases in HbA1c and bodyweight compared with placebo in patients with type 2 diabetes uncontrolled by diet and exercise.10, 11 Oral semaglutide at 7 mg and 14 mg per day also resulted in significantly greater decreases in HbA1c and bodyweight over 26 weeks versus the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes uncontrolled on metformin with or without sulfonylurea.12
This phase 3a trial, PIONEER 4, is the first to compare the efficacy and safety of oral semaglutide with a subcutaneously injected GLP-1 receptor agonist, liraglutide, and placebo in patients with type 2 diabetes uncontrolled on background metformin with or without a sodium-glucose co-transporter-2 (SGLT2) inhibitor.
Section snippets
Study design
PIONEER 4 was a 52-week, randomised, double-blind, double-dummy, active-controlled, and placebo-controlled phase 3a trial undertaken at 100 trial sites in 12 countries (Croatia, Czech Republic, Germany, Hungary, Japan, Latvia, Poland, Slovakia, South Africa, Ukraine, United Arab Emirates, and the USA).
Two different questions related to efficacy were addressed through the definition of two estimands: the treatment policy estimand and the trial product estimand, which were defined on the basis of
Results
Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were enrolled and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. All participants were given at least one dose of assigned treatment and treatment was completed without rescue medication for 223 (78%) of
Discussion
In PIONEER 4, oral semaglutide was compared with daily injections of subcutaneous liraglutide and placebo in patients with type 2 diabetes receiving metformin with or without an SGLT2 inhibitor. Using the treatment policy estimand, oral semaglutide was non-inferior to once-daily subcutaneous liraglutide given at the highest approved dose for the treatment of type 2 diabetes and superior to placebo in decreasing HbA1c at week 26. Additionally, significantly greater decreases in HbA1c were
Data sharing
Data will be shared with researchers who submit a research proposal approved by an independent review board. Access request proposals can be found at novonordisk-trials.com. Data will be made available after research completion and approval of the product and product use in the EU and the USA. Individual participant data will be shared in datasets in a de-identified and anonymised format. There will not be any limitations on how these data can be used.
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