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.

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 (= 184), 7 mg (= 182), or 14 mg (= 181) or to placebo (= 184) in a 52-week, double-blind trial. End points were change from baseline to week 26 in HbA(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 HbA(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;< 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];= 0.0392 for 3 mg,≤ 0.0001 for 7 and 14 mg) at week 26 (treatment policy estimand). Significantly greater dose-dependent HbAand 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 HbAand 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.