Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial

Abstract

OBJECTIVE Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n = 412) or empagliflozin 25 mg (n = 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA_1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA_1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P < 0.0001). The treatment difference in HbA_1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% [–15 vs. –9 mmol/mol], ETD –0.5% [95% CI –0.7, –0.4] [–6 mmol/mol (–7, –5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product −4.7 vs. −3.8 kg; P = 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS Oral semaglutide was superior to empagliflozin in reducing HbA_1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA_1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.