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

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 (= 412) or empagliflozin 25 mg (= 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA(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 HbAversus 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)];< 0.0001). The treatment difference in HbAsignificantly 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)];< 0.0001) and at week 52 for both estimands (< 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;= 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS: Oral semaglutide was superior to empagliflozin in reducing HbAbut not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbAand 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.