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

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.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.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 < 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 < 0.0001) and at week 52 for both estimands (P < 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.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.