PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes
Authors: Vanita R. Aroda, Julio Rosenstock, Yasuo Terauchi, Yuksel Altuntas, Nebojsa M. Lalic, Enrique C. Morales Villegas, Ole K. Jeppesen, Erik Christiansen, Christin L. Hertz, Martin Haluzík, Krim Belkacem, Nabil Chiali, Samia Bourezane, Rachida Guermaz, Plamen Popivanov, Ivaylo Lefterov, Tsvetalina Tankova, Ivan Penchev, Martina Koskova, Miroslava Hudcova, Alica Vesela, Anna Rancova, Martin Haluzik, Arihiro Kiyosue, Osamu Matsuoka, Satoshi Inoue, Yasuo Terauchi, Yasushi Fukushima, Yumiko Ide, Rafael Margarito Violante Ortiz, Enrique Morales Villegas, Albina Golovach, Diana Alpenidze, Elena Frolova, Elena Zhdanova, Ludmila Ruyatkina, Olga Ershova, Yulia Samoilova, Svetlana Zyangirova, Katarina Lalic, Nebojsa Lalic, Teodora Beljic Zivkovic, Esra Ataoglu, Okan Bakiner, Akin Dayan, Mehmet Sargin, Meral Mert, Mine Adas, Omur Tabak, Yuksel Altuntas, Alexander Murray, Ali Iranmanesh, Aron Schlau, Bram Wieskopf, Brian Snyder, Carl Griffin, Charles Fogarty, Charles Lovell, Dale Allison, David Fitz-Patrick, David Grant, David Klonoff, Dwayne Williams, Eddie Armas, Eileen Palace, Gary Ruoff, Gilbert Martinez, Gilberto Perez, Harold Bays, Horia Tatu, James Maynard, Jeanne-Elyse Cedeno, Vanita Aroda, Jean Park, Jennefer Sutton, Joe Pouzar, John Bertsch, Jonathan Condit, Jorge Serje, Josel Cabaccan, Joseph Risser, Juan Frias, Julio Rosenstock, Kanagaratnam Sivalingam, Kelli Maw, Lenita Hanson, Liana Billings, Lisa Connery, Mario Juarez, Michael Lillestol, Neil Fraser, Paul Beckett, Ralph Wade, Raul Gaona, Richard Jackson, Robert DeLuca, Sady Alpizar, Sharon Herring, Stanley Stringam, Steven Bauer, Sumana Gangi, Teresa Sligh, Wentworth Jarrett, William Fitzgibbons
Journal: Diabetes Care (2019)

OBJECTIVE This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients. RESEARCH DESIGN AND METHODS This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26 in body weight. RESULTS In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, −0.6% [3 mg], −0.9% [7 mg], and −1.1% [14 mg]; trial product estimand, −0.7% [3 mg], −1.2% [7 mg], and −1.4% [14 mg]; P &amp;lt; 0.001 for all) and body weight (treatment policy, −0.1 kg [3 mg], −0.9 kg [7 mg], and −2.3 kg [14 mg, P &amp;lt; 0.001]; trial product, −0.2 kg [3 mg], −1.0 kg [7 mg, P = 0.01], and −2.6 kg [14 mg, P &amp;lt; 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3–7.4% with oral semaglutide and 2.2% with placebo. CONCLUSIONS In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.