Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial

• Published in: JAMA : the journal of the American Medical Association 2019-04, Vol.321 (15), p.1466-1480
• Main Authors: Rosenstock, Julio, Allison, Dale, Birkenfeld, Andreas L, Blicher, Thalia Marie, Deenadayalan, Srikanth, Jacobsen, Jacob Bonde, Serusclat, Pierre, Violante, Rafael, Watada, Hirotaka, Davies, Melanie
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Adults; Antidiabetics; Body mass; Body mass index; Body size; Body weight; Clinical trials; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Dosage; Dose-Response Relationship, Drug; Double-Blind Method; Double-blind studies; Drug Therapy, Combination; Female; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - agonists; Glucagon-Like Peptides - administration & dosage; Glucagon-Like Peptides - adverse effects; Glycated Hemoglobin A - analysis; Hemoglobin; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Male; Metformin; Metformin - therapeutic use; Middle Aged; Online First; Original Investigation; Patients; Sitagliptin Phosphate - administration & dosage; Sitagliptin Phosphate - adverse effects; Sulfonylurea; Sulfonylurea Compounds - therapeutic use
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2019.2942

IMPORTANCE: Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. OBJECTIVE: To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. INTERVENTIONS: Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. MAIN OUTCOMES AND MEASURES: The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. RESULTS: Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, –0.3% [95% CI, –0.4% to –0.1%] and –0.5% [95% CI, –0.6% to –0.4%], respectively; P