Investigational Rapid-Acting U500 Insulin Maintains Efficacy Regardless of BMI

AT278, an investigational U500 rapid-acting insulin aspart formulation in development by Arecor Therapeutics, has demonstrated greater glucose reduction and rapid onset regardless of body mass index (BMI) among patients with type 2 diabetes (T2D).¹

Patients with T2D and obesity often exhibit severe insulin resistance, drastically increasing their daily requirements. Concentrated insulins have become the cornerstone of treatment for these patients – however, the only approved high-concentration U500 option, HumIns-U500, significantly alters the pharmacokinetic profile of regular insulin and prevents it from meeting physiological meal-related needs. AT278-U500 is currently in development to address this gap.^1,2

“We have tested the compound before in type 1 diabetes, and it turned out to be one of the fastest insulins we have ever had in our hands,” Thomas Pieber, MD, chair of the Division of Endocrinology and Diabetology at the Department of Internal Medicine at the Medical University of Graz, told HCPLive in an exclusive interview. “We asked the question, is it also that fast in type 2? It is. We asked the question, is it also fast when you look at different BMIs, normal and very high BMI? And indeed, it maintains its fast action.”

Pieber and colleagues conducted a phase 1, single-dose, randomized, double-blind, 2-way crossover glucose clamp study, including an extension period for an open-label third comparator. Patients were eligible for inclusion if they were aged 18-75 years and had T2D for ≥6 months. Additionally, patients were required to have a BMI of 25-45 kg/m² and an HbA1c ≤80 mmol/mol (≤9.5%). Patients with known or suspected hypersensitivity to the study medications or clinically significant concomitant diseases were excluded, among other criteria.¹

After initial screening, patients would attend ≤3 clamp visits, each separated by a 5-21-day washout period. Patients were given a single subcutaneous dose of 0.5 U/kg of AT278-U500 or InsAsp-U100 in randomized sequence at the first 2 clamp visits. At the third visit, patients were given HumIns-U500 instead. At each visit, patients consumed a standardized meal, began fasting at 10:00 PM, and were initiated into the euglycemic glucose clamp at 11:00 PM with an overnight run-in period.¹

The study’s primary endpoint was area under the glucose infusion rate (GIR)-time curve from 0 to 60 minutes. Endpoints were analyzed via a linear mixed model, with treatment, treatment sequence, and visit as fixed effects and participant as random effect. A sensitivity analysis was conducted as well, including solely patients who completed euglycemic clamps with AT278-U500 and InsAsp-U100.¹

A total of 69 patients were screened, of whom 41 were admitted and randomized into the trial. Of these patients, 2 withdrew after the first clamp visit due to adverse events unrelated to treatment. 39 patients completed both euglycemic clamps with AT278-U500 and InsAsp-U100, while 36 completed the additional open label comparison with HumIns-U500.¹

Over the course of the study, AT278-U500 displayed a substantially faster insulin absorption than InsAsp-U100 and HumIns-U500 (t_Early50%Cmax: 9 min vs. 35 min vs. 55 min), which lead to a substantially higher glucose-lowering effect within the first hour than both InsAsp-U100 (treatment ratio, 2.02; 95% CI, 1.64-2.5) and HumIns-U500 (treatment ratio, 3.91; 95% CI, 1.89-5.27).¹

When divided by median BMI, Pieber and colleagues found that the AUC was substantially higher with AT278-U500 in both the low- and high-BMI subgroup compared to InsAsp-U100. Linear regression indicated a significant inverse relationship between AUC and BMI for InsAsp-U100, while AT278-U500 had no similar relationship. Overall insulin exposure was also similar for AT278-U500 and InsAsp-U100, while overall glucose lowering was comparable across all treatments.¹

Ultimately, Pieber and colleagues concluded that AT278-U500 maintains its ultra-rapid onset characteristics regardless of a patient’s BMI. This represents the first-ever ultra-rapid U500 option for prandial dosing in patients with T2D who are insulin-resistant. However, the team also noted the lack of faster-acting insulin analogues currently in use in clinical practice, such as faster aspart U100, URLi U100 and U200. The team acknowledges that head-to-head comparison studies with these formulations would provide important data regarding AT278-U500’s relative performance.¹

“One of our next steps will be comparing faster insulins against this new U500 insulin,” Pieber said. “It was simply a technical limitation why we haven’t tested it. It somewhat limits the clinical conclusions we can draw. That’s another study that can be done in the near future.”

Editors’ Note: Pieber reports disclosures with Adocia, Arecor, AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi, 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. Eli Lilly and Company, “HUMULIN R U-500 (Insulin Human) Injection, for Subcutaneous Use [Prescribing Information],” Accessed August 17, 2026, https://pi.lilly.com/us/humulin-r-u500-pi.pdf