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ABSTRACTBackgroundEfficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin.Research design and methodsIn this open-label, active-controlled trial, patients with T2D, HbA1c≥7%–≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, n= 30; 45 mg, n= 31) and IAsp, n= 30. Primary outcome was change from baseline (CFB) in HbA1cat week 24. Secondary outcomes included PPG excursion (PPGE) and PPG assessed from standardized test meal (STM) and 9-point self-monitored blood glucose.ResultsThe observed mean HbA1cdid not improve at week 24 in Tregopil groups (30 mg [0.15%], 45 mg [0.22%] vs. a reduction in IAsp group [−0.77%]). Combined Tregopil group showed better 1-h PPGE control versus IAsp following STM (CFB, estimated treatment difference, 95% CI, −45.33 mg/dL [−71.91, −18.75], p = 0.001) and 1-h PPG trended toward better control. Tregopil showed lower PPGE at 15 min versus IAsp. Clinically significant hypoglycemia was lower with Tregopil versus. IAsp (rate ratio: 0.69).ConclusionsTregopil demonstrated an ultrafast, short-duration prandial profile with good safety. While Tregopil’s early postprandial effects were comparable to IAsp, its late postprandial effects were inferior.Trial registrationThe trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03430856).

We evaluated the pharmacokinetics and pharmacodynamics of oral insulin tregopil in relation to premeal dosing time, between‐meal interval, and meal composition type in type 2 diabetes mellitus patients in a randomized, placebo‐controlled, crossover study consisting of 3 sequential cohorts. In Cohort 1, insulin tregopil administered 10 to 20 minutes before a meal resulted in optimal postmeal exposure and demonstrated better postprandial glucose‐lowering effect (glucose area under concentration‐time curve [AUC]) compared to the 30‐minute group. In Cohort 2, insulin tregopil pharmacokinetic exposure (plasma AUC) showed a progressive increase through 4, 5, and 6 hours of between‐meal interval. The 6‐hour between‐meal interval resulted in better absorption of insulin tregopil in comparison to 4‐ and 5‐hour intervals. However, no significant differences were observed in pharmacodynamic parameters except for higher glucose AUC0‐180minin the insulin tregopil 4‐hour group during the afternoon meal as compared to the morning meal. In Cohort 3, a high‐fiber meal had the least impact on insulin tregopil absorption and resulted in the highest reduction in plasma glucose levels in the afternoon. A high‐fat meal reduced insulin tregopil absorption in the afternoon meal; however, pharmacodynamic response was not diminished significantly. Insulin tregopil has a rapid onset of action of approximately 10 minutes and, when administered 10 to 20 minutes before a meal, demonstrated up to 13% to 18% reduction in blood glucose levels compared to baseline. A 5‐hour between‐meal interval minimizes the impact of a meal on absorption of subsequent (afternoon) insulin tregopil dose, and the pharmacodynamic response of insulin tregopil is not altered by meal composition. Insulin tregopil was well tolerated in patients with type 2 diabetes mellitus.