Ultra-Rapid U500 Aspart AT278 Aids High-Dose T2D Therapy

Insulin-resistant patients with type 2 diabetes requiring very high mealtime doses have long lacked a concentrated insulin with a rapid onset, forcing clinicians to choose between large injection volumes and sluggish pharmacokinetics. A newly published pharmacokinetic and pharmacodynamic study on AT278, an investigational insulin aspart formulated at 500 units/mL, suggests this gap may be closing.

On a recent episode of Diabetes Dialogue, co-hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, discussed the findings and their potential effect on insulin delivery for patients with high insulin requirements.

Watch the full episode discussing AT278 here.

The single-center, randomized, double-blind, crossover study used a 12-hour euglycemic clamp to compare AT278 against standard-concentration insulin aspart (U100) and regular human U500 insulin in adults with type 2 diabetes and body mass index ranging from 25 to 38 kg/m². Each participant received a single subcutaneous dose of one formulation. AT278 produced significantly faster insulin absorption than both comparators, translating into a significantly greater glucose-lowering effect within the first hour.

This ultra-rapid profile held consistently across the full body mass index range studied, addressing a longstanding limitation of regular U500 insulin, which behaves more like an intermediate-acting agent despite its labeling. Regular U500 requires dosing roughly 30 minutes before meals while also serving a basal function, complicating use in patients who skip or delay meals. Because concentrated insulin volume, not units, is often the limiting factor in insulin pump selection, an ultra-rapid U500 option could allow more patients on high daily doses to use smaller, more desirable devices.

Current concentrated-insulin practice often involves off-label use of U200 insulin in pumps or manual U500 injections, both of which carry meaningful hypoglycemia risk and dosing complexity. An ultra-rapid, high-concentration analog designed for prandial dosing would represent the first option of its kind for insulin-resistant patients with type 2 diabetes on high-dose therapy. If confirmed in larger trials, AT278 could reshape how clinicians manage insulin delivery in this population, including expanding candidacy for automated insulin delivery systems currently considered unsuitable for regular U500 insulin.

Editors’ Note: Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others. Bellini reports disclosures with Abbott Diabetes Care, MannKind, Povention Bio, and others.

References

1. Svehlikova E, Gatschelhofer C, Lackner B, et al. A new highly concentrated insulin aspart at278 (500 u/ ML ) demonstrates Ultra‐rapid pharmacokinetic and pharmacodynamic properties in type 2 diabetes regardless of bmi. Diabetes, Obesity and Metabolism. Published online July 30, 2026. doi:10.1111/dom.71150