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: Zinman Bernard , Aroda Vanita R. , Buse John B. , Cariou Bertrand , Harris Stewart B. , Hoff Søren Tetens , Pedersen Karen Boje , Tarp-Johansen Mads Jeppe , Araki Eiichi ,   PIONEER 8 Investigators, Zinman Bernard , Fikry Sameh , Bajaj Harpreet , Landry Daniel , Caplan David , Woo Vincent , Harris Stewart , Thuan Jean-Francois , Serusclat Pierre , Cariou Bertrand , Gourdy Pierre , Fradet Gerard , Monier Arnaud , Borot Sophie , Monguillon Pascal , Gouet Didier , Doupis John , Tentolouris Nikolaos , Tsimichodimos Vasileios , Melidonis Andreas , Bekiari Eleni , Bargiota Alexandra , Agarwal Sanjay , Saboo Banshi , Chatterjee Sanjay , Mohan Viswanathan , Shaikh Shehla , Gupta Yashdeep , Bhattacharyya Arpandev , Manikath Neeraj , Jain Sunil , Sasaki Takashi , Osonoi Takeshi , Fukuda Shuichi , Wada Seiki , Kiyosue Arihiro , Ide Yumiko , Onishi Yukiko , Matoba Kiyokazu , Takai Kuninobu , Yamauchi Akira , Inoue Satoshi , Kaneko Shizuka , Ikeda Hiroki , Ohta Yasuharu , Hisatomi Akitaka , Senokuchi Takafumi , Jinnouchi Hideaki , Nakamura Shuji , Soto José Roberto Lazcano , Briones Ignacio Rodriguez , Bogdanski Pawel , Szyprowska Ewa , Modzelewska Anna , Wozniak Iwona , Zyangirova Svetlana , Sergeeva-Kondrachenko Marina , Davis Thomas , Thomson Stephen , Frias Juan , Gandy Winston , Lingvay Ildiko , Pounds Kevin , Bowman-Stroud Cynthia , Dempsey Michael , Huffman David , Ahmed Azazuddin , Fraser Neil , Ortiz-Carrasquillo Ramon , Bolster D. Eric , Adams Michael , Hummel Matthew , Free Almena , Houser Patricia , Shockey Gerald , Barnum Otis , Bhasker Kala , Cornett George , Streja Dan , Kirby William , Lynd Sean , Folkerth Steven , Nakhle Samer , Norwood Paul , Perez Rodolfo , Snyder Brian , Farris Neil , Litchfield Willian , Hamdy Osama , Park Jean , Aroda Vanita , Buse Joh 
Published: September 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 &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.