Diabetes Dialogue: Ultra-Rapid Insulin, IcoSema Advance in Type 2 Diabetes

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Insulin-resistant patients with type 2 diabetes who require high-dose therapy have long lacked a rapid-acting option concentrated enough for compact insulin pumps. New pharmacokinetic data on an ultra-rapid U-500 insulin aspart, alongside additional phase 3 results for a combined once-weekly insulin icodec-semaglutide regimen, both aim to close persistent gaps in insulin delivery for this population.

On a recent episode of Diabetes Dialogue, co-hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, reviewed two studies addressing unmet needs in insulin therapy for type 2 diabetes.

The investigational agent AT278 is a highly concentrated insulin aspart formulated at 500 units/mL, distinct from existing U-500 regular human insulin, which behaves more like an intermediate-acting product. In a single-center, randomized, double-blind, crossover euglycemic clamp study spanning body mass index from 25 to 38 kg/m², AT278 produced significantly faster absorption and a greater glucose-lowering effect within the first hour versus both standard U-100 insulin aspart and U-500 regular human insulin. The ultra-rapid pharmacokinetic and pharmacodynamic profile held consistent across the BMI range studied.

Current U-500 regular insulin requires dosing 30 minutes before meals while simultaneously serving as basal and prandial coverage, complicating use in automated insulin delivery systems and limiting compatibility with smaller-volume pumps. A concentrated, rapid-onset formulation could allow patients with high insulin requirements to use compact pumps and extended-wear infusion sets without the absorption problems tied to large-volume subcutaneous depots. Drawn from an early-phase study, the findings position AT278 as a potential first ultra-rapid option for prandial dosing in this population, though regulatory approval for pump use remains undefined.

Separately, the phase 3 COMBINE 4 trial evaluated a fixed combination of once-weekly insulin icodec (Awiqli) and semaglutide, known as IcoSema, against once-daily insulin glargine U-100 in 485 adults with type 2 diabetes and baseline A1C above 8%. Over 40 weeks, IcoSema reduced A1C by 3.32 percentage points versus 2.44 points with glargine, a between-group difference of 0.88 percentage points, while producing a 0.79 kg weight reduction compared with a 3.81 kg gain with glargine. Time in range reached 79.8% with IcoSema versus 64.5% with glargine, consistent with the mechanistic rationale of pairing glucagon-like peptide-1 receptor agonism with basal insulin to limit postprandial excursions.

These results build on earlier COMBINE 1 through 3 data, which showed IcoSema achieving noninferior or superior A1C reduction, superior weight outcomes, and lower hypoglycemia rates versus comparators. A single weekly injection combining basal insulin with a GLP-1 receptor agonist could reduce treatment burden and consolidate pharmacy copays, though semaglutide exposure remains capped by concurrent insulin titration, averaging 0.66 mg in COMBINE 4. Whether either agent reaches United States practice, including reported uncertainty around a domestic IcoSema launch, will determine their eventual role in managing insulin-resistant type 2 diabetes.

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

2. Ji L, Benamar M, Mohan V, et al. Once-weekly ICOSEMA versus once-daily insulin glargine U100 in type 2 diabetes management (Combine 4): An open-label, multicentre, treat-to-target, randomised, phase 3B trial. The Lancet Diabetes & Endocrinology. Published online August 13, 2026. doi:10.1016/s2213-8587(26)00136-1