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