Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial
Authors: Bernard Zinman, Vanita R. Aroda, John B. Buse, Bertrand Cariou, Stewart B. Harris, Søren Tetens Hoff, Karen Boje Pedersen, Mads Jeppe Tarp-Johansen, Eiichi Araki, Bernard Zinman, Sameh Fikry, Harpreet Bajaj, Daniel Landry, David Caplan, Vincent Woo, Stewart Harris, Jean-Francois Thuan, Pierre Serusclat, Bertrand Cariou, Pierre Gourdy, Gerard Fradet, Arnaud Monier, Sophie Borot, Pascal Monguillon, Didier Gouet, John Doupis, Nikolaos Tentolouris, Vasileios Tsimichodimos, Andreas Melidonis, Eleni Bekiari, Alexandra Bargiota, Sanjay Agarwal, Banshi Saboo, Sanjay Chatterjee, Viswanathan Mohan, Shehla Shaikh, Yashdeep Gupta, Arpandev Bhattacharyya, Neeraj Manikath, Sunil Jain, Takashi Sasaki, Takeshi Osonoi, Shuichi Fukuda, Seiki Wada, Arihiro Kiyosue, Yumiko Ide, Yukiko Onishi, Kiyokazu Matoba, Kuninobu Takai, Akira Yamauchi, Satoshi Inoue, Shizuka Kaneko, Hiroki Ikeda, Yasuharu Ohta, Akitaka Hisatomi, Takafumi Senokuchi, Hideaki Jinnouchi, Shuji Nakamura, José Roberto Lazcano Soto, Ignacio Rodriguez Briones, Pawel Bogdanski, Ewa Szyprowska, Anna Modzelewska, Iwona Wozniak, Svetlana Zyangirova, Marina Sergeeva-Kondrachenko, Thomas Davis, Stephen Thomson, Juan Frias, Winston Gandy, Ildiko Lingvay, Kevin Pounds, Cynthia Bowman-Stroud, Michael Dempsey, David Huffman, Azazuddin Ahmed, Neil Fraser, Ramon Ortiz-Carrasquillo, D. Eric Bolster, Michael Adams, Matthew Hummel, Almena Free, Patricia Houser, Gerald Shockey, Otis Barnum, Kala Bhasker, George Cornett, Dan Streja, William Kirby, Sean Lynd, Steven Folkerth, Samer Nakhle, Paul Norwood, Rodolfo Perez, Brian Snyder, Neil Farris, Willian Litchfield, Osama Hamdy, Jean Park, Vanita Aroda, Joh Buse
Journal: Diabetes Care (2019)

OBJECTIVE To investigate the efficacy, safety, and tolerability of oral semaglutide added to insulin with or without metformin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes uncontrolled on insulin with or without metformin were randomized to oral semaglutide 3 mg (N = 184), 7 mg (N = 182), or 14 mg (N = 181) or to placebo (N = 184) in a 52-week, double-blind trial. End points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands were defined: treatment policy (effect regardless of trial product discontinuation or rescue medication) and trial product (effect assuming trial product continuation without rescue medication) in randomized patients. RESULTS Oral semaglutide was superior to placebo in reducing HbA1c (estimated treatment difference [ETD] –0.5% [95% CI –0.7, –0.3], –0.9% [–1.1, –0.7], and –1.2% [–1.4, –1.0] for 3, 7, and 14 mg, respectively; P &amp;lt; 0.001) and body weight (ETD −0.9 kg [95% CI −1.8, −0.0], −2.0 kg [−3.0, −1.0], and −3.3 kg [−4.2, −2.3]; P = 0.0392 for 3 mg, P ≤ 0.0001 for 7 and 14 mg) at week 26 (treatment policy estimand). Significantly greater dose-dependent HbA1c and body weight reductions versus placebo were achieved with oral semaglutide at weeks 26 and 52 (both estimands). The most frequent adverse event with oral semaglutide was nausea (11.4–23.2% of patients vs. 7.1% with placebo; mostly mild to moderate). CONCLUSIONS Oral semaglutide was superior to placebo in reducing HbA1c and body weight when added to insulin with or without metformin in patients with type 2 diabetes. The safety profile was consistent with other glucagon-like peptide 1 receptor agonists.