Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial.

BACKGROUND: New glucose-lowering medications need to be investigated in east Asian populations, as the clinical characteristics of type 2 diabetes differ between western and east Asian patients. The PIONEER 10 study aimed to evaluate the safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes. METHODS: PIONEER 10 was an open-label, randomised, active-controlled, phase 3a trial done at 36 sites (clinics and university hospitals) in Japan. Patients aged 20 years and older with uncontrolled type 2 diabetes were randomly assigned (2:2:2:1) to receive once-daily oral semaglutide 3 mg, 7 mg, or 14 mg, or once-weekly subcutaneous dulaglutide 0·75 mg for 52 weeks, as an add-on to their background medication. The primary endpoint was the number of treatment-emergent adverse events over 57 weeks. Supportive secondary endpoints (not controlled for multiplicity) included mean change from baseline in HbA and bodyweight at 52 weeks. This trial is registered with ClinicalTrials.gov, NCT03015220. FINDINGS: Between Jan 10, and May 30, 2017, 492 patients were screened and 458 were randomly assigned to oral semaglutide 3 mg (n=131), 7 mg (n=132), or 14 mg (n=130), or dulaglutide 0·75 mg (n=65). 448 (98%) patients completed the trial. Adverse events occurred in 101 (77%) of 131 patients with oral semaglutide 3 mg, 106 (80%) of 132 with oral semaglutide 7 mg, 111 (85%) of 130 with oral semaglutide 14 mg, and 53 (82%) of 65 with dulaglutide. The most common adverse events were infections and gastrointestinal events. Gastrointestinal adverse events (mostly mild and transient constipation and nausea) occurred in a dose-dependent manner with oral semaglutide. Adverse events led to premature treatment discontinuation in four (3%) of 131 patients receiving oral semaglutide 3 mg, eight (6%) of 132 receiving oral semaglutide 7 mg, eight (6%) of 130 receiving oral semaglutide 14 mg, and two (3%) of 65 receiving dulaglutide. No deaths or severe hypoglycaemic events were reported. Based on the treatment policy estimand (ie, regardless of study drug discontinuation or rescue medication use), estimated mean reductions in HbA from baseline (8·3%) to week 52 were -0·9 percentage points (SE 0·1) with oral semaglutide 3 mg, -1·4 percentage points (0·1) with oral semaglutide 7 mg, -1·7 percentage points (0·1) with oral semaglutide 14 mg, and -1·4 percentage points (0·1) with dulaglutide (estimated treatment difference -0·3% [95% CI -0·6 to -0·1] for oral semaglutide 14 mg vs dulaglutide; p=0·0170). Estimated mean changes in bodyweight from baseline (72·1 kg) to week 52 were 0·0 kg (SE 0·3) with oral semaglutide 3 mg, -0·9 kg (0·3) with oral semaglutide 7 mg, -1·6 kg (0·3) with oral semaglutide 14 mg, and 1·0 kg (0·4) with dulaglutide (estimated treatment difference -2·6 kg [95% CI -3·5 to -1·6] for oral semaglutide 14 mg vs dulaglutide; p<0·0001). INTERPRETATION: Oral semaglutide was well tolerated in Japanese patients with type 2 diabetes. Once-daily oral semaglutide significantly reduced HbA (14 mg dose) and bodyweight (7 mg and 14 mg doses) versus weekly subcutaneous dulaglutide 0·75 mg by week 52. FUNDING: Novo Nordisk.