Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial
Authors: Rodbard Helena W. , Rosenstock Julio , Canani Luis H. , Deerochanawong Chaicharn , Gumprecht Janusz , Lindberg Søren Østergaard , Lingvay Ildiko , Søndergaard Anette Luther , Treppendahl Marianne Bach , Montanya Eduard ,   PIONEER 2 Investigators, Cruz Pablo , Loredo Luis De , Luquez Cecilia , Moisello Maria , Augusto Gustavo Akerman , Castro Marise , Canani Luis , Akrap Branko , Bulum Tomislav , Rahelic Dario , Sunic-Grcic Ivana , Tusek Srecko , Avramidis Iakovos , Benroubi Marian , Didangelos Triantafyllos , Karousos Gerasimos , Pagkalos Emmanouil , Sampanis Christos , Somali Maria , Domboróczki Zsolt , Faludi Péter , Gaál Zsolt , Kis-Gombos Piroska , Kocsis Gyozo , Marton Zoltán , Sudár Zsolt , Buscemi Silvio , Di Carlo Alberto , Dotta Francesco , Gambineri Alessandra , Lauro Davide , Maranghi Marianna , Arciszewska Malgorzata , Gumprecht Janusz , Matuszewska Krystyna , Skokowska Ewa , Stasinska Teresa , Feofanova Svetlana , Filippova Ekaterina , Galstyan Gagik , Gaysina Leylya , Kunitsyna Marina , Suplotova Lyudmila , Antic Slobodan , Djukic Aleksandar , Mitrovic Milena , Pesic Milica , Stokic Edita , Jodar Esteban , Martínez Encarna , Raya Pedro Mezquita , Montanya Eduard , Portillo Cristobal Morales , Vera Mercè Pérez , Fernández Margarita Rivas , San Jose Patricia , Riera Manel Terns , Boonyavarakul Apussanee , Deerochanawong Chaicharn , Sriwijitkamol Apiradee , Ajani Dilawar , Armas Eddie , Barbel-Johnson Kim , Bartilucci Darlene , Bonabi Gholamreza , Busch Robert , Butuk David , Cannon Kevin , Chase Craig , Chaykin Louis , Cheekati Vasundhara , Davis Thomas , Delgado Belkis , Farris Neil , Graves Mark , Ha Chi , Harper Linda , Herring Sharon , Hewitt Mitzie , Hsia Daniel , Jackson Richard , Jardula Michael , Joyce Mark , Juarez Mario , Kapoor Anoop , Karounos Dennis , Kayne David , Lacour Audrey , Ledesma Gilbert , Lingvay Ildiko , Lipetz Robert , Lomboy Joseph , Lynd Sean , Morawski Emily , Morin Robert , Murphy Richard , Overcash J. Scott , Pullman John , Rodbard Helena W. , Rosenstock Julio , Ruoff Gary , Steenkamp Devin , Toro Hugo , Trachtenbarg David , Tulloch Brian , Weisbrot Albert , Wright Alison 
Published: September 2019

OBJECTIVE
Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin.

RESEARCH DESIGN AND METHODS
Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n = 412) or empagliflozin 25 mg (n = 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients.

RESULTS
Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P &lt; 0.0001). The treatment difference in HbA1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% [–15 vs. –9 mmol/mol], ETD –0.5% [95% CI –0.7, –0.4] [–6 mmol/mol (–7, –5)]; P &lt; 0.0001) and at week 52 for both estimands (P &lt; 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product −4.7 vs. −3.8 kg; P = 0.0114). Gastrointestinal adverse events were more common with oral semaglutide.

CONCLUSIONS
Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.