A New Highly Concentrated Insulin Aspart <scp>AT278</scp> (500 U/ <scp>mL</scp> ) Demonstrates Ultra‐Rapid Pharmacokinetic and Pharmacodynamic Properties in Type 2 Diabetes Regardless of <scp>BMI</scp>

ABSTRACT Aims To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 [500 U/mL]; AT278‐U500) compared with standard concentration insulin aspart (InsAsp [100 U/mL]; InsAsp‐U100) and U500 human regular insulin (HumIns [500 IU/mL]; HumIns‐U500). Materials and Methods This single‐centre, randomised, double‐blind crossover 12‐h euglycaemic clamp study was conducted in 41 overweight and obese people with type 2 diabetes (BMI 25.0–38.7 kg/m 2 ) receiving a single subcutaneous dose (0.5 U/kg) of AT278‐U500 and InsAsp‐U100. HumIns‐U500 was consecutively studied open label in a 24‐h clamp. Results AT278‐U500 exhibited a significantly faster insulin absorption than InsAsp‐U100 and HumIns‐U500 ( t Early50%Cmax : 9 min vs. 35 min vs. 55 min), leading to a significantly higher glucose‐lowering effect within the first hour (AUC GIR,0‐60min ) compared with both InsAsp‐U100 (treatment ratio 2.02 [95% CI 1.64; 2.50]) and HumIns‐U500 (3.91 [2.89; 5.27]). When divided by median BMI (29.7 kg/m 2 ), AUC GIR,0‐60min was significantly higher with AT278‐U500 in both the low‐BMI and high‐BMI subgroup compared to InsAsp‐U100. Linear regression showed a significant inverse relationship between BMI and AUC GIR,0‐60min for InsAsp‐U100 (slope −0.142, p &lt; 0.0001), whereas AT278‐U500 showed no such relationship. Overall insulin exposure was similar for AT278‐U500 and InsAsp‐U100, while overall glucose‐lowering effect was comparable across all three treatments. Conclusions AT278‐U500 maintains its ultra‐rapid onset characteristics independent of BMI, representing the first ultra‐rapid U500 option for prandial dosing in insulin‐resistant people with type 2 diabetes requiring high‐dose therapy. Trial Registration: ClinicalTrials.gov identifier: NCT05754424