Ultra-Rapid Acting Insulins and AID Performance

Introduction to Ultra-Rapid Acting Insulins in Automated Insulin Delivery Systems

An automated insulin delivery (AID) system links a continuous glucose monitor (CGM) to an insulin pump through software that adjusts delivery as readings come in. Its weak spot is timing. Insulin infused under the skin takes a while to reach the blood, so the algorithm is usually responding to a rise that has already started. Ultra-rapid acting insulins (URAIs) are mealtime insulins reformulated to shorten that lag [9]. The two most studied are Fiasp from Novo Nordisk, which is insulin aspart with added niacinamide [6], and Lyumjev from Eli Lilly, which is insulin lispro (labeled insulin lispro-aabc) with added treprostinil and sodium citrate [7]. We cover the formulations in more depth in Ultra-Rapid Acting Insulin Formulations.

How do the additives work? In lab and animal experiments, Novo Nordisk scientists found that niacinamide raises the share of insulin aspart in its single-molecule (monomer) form and helps it cross blood-vessel walls; it also briefly relaxes small blood vessels near the injection site [8]. In Lyumjev, treprostinil widens local blood vessels while citrate makes them leakier, according to a review written largely by Lilly authors [9]. Both insulins have been tested inside AID systems, including MiniMed's [1][5]. In December 2025 the FDA approved a change adding Fiasp and Lyumjev to the insulins the MiniMed 780G system is labeled to use [4].

Key Findings and Implications

Performance Enhancement

The gain in time in range is real but small. Time in range (TIR) is the share of the day a CGM reads between 70 and 180 mg/dL. A 2025 meta-analysis pooled 16 randomized trials with 664 people with type 1 diabetes and found that AID systems running an ultra-rapid insulin added about 1.1 percentage points of TIR, a difference the authors called statistically significant but not clinically significant [2]. The same analysis found slightly less time below range and no difference in diabetic ketoacidosis or severe hypoglycemia [2]. A second 2025 meta-analysis put the TIR gain at 0.87 points, short of statistical significance, while reporting less glucose variability and less time below range [3].

Single trials tell a similar story. In 25 adults using MiniMed's advanced hybrid closed-loop system, Fiasp produced 82.3% TIR against 79.6% for standard insulin aspart, and most of the difference came at mealtimes; the authors noted that a 1.9-point gain may matter little in practice [1]. A larger 2026 study gave Lyumjev to 211 children and adults on the 780G and reported higher TIR than during a run-in period [5]. That run-in used standard insulin with the pump in manual mode or with only basal automation, so the comparison mixes the insulin switch with turning full automation on [5].

Trade-offs and Challenges

Here's what surprised us: the main trade-off shows up on the skin, not in the glucose numbers. In Lilly's pump trial of adults with type 1 diabetes, 19.1% of people using Lyumjev reported an infusion-site reaction and 15.8% reported infusion-site pain [7]. Treatment-emergent adverse events in that trial were higher with Lyumjev than with standard lispro (60.5% against 44.7%), driven mostly by mild or moderate site reactions and pain [10]. The Lyumjev label notes that treprostinil and citrate have been linked to injection and infusion site reactions in other, non-insulin products [7]. For Fiasp, the label reports infusion-site reactions in 10.2% of adults in its pump trial [6].

A few people stop the insulin over them. In a 13-week study of Lyumjev in Tandem's t:slim X2 pump, 2 of 179 participants stopped Lyumjev because of infusion-site discomfort [14]. That study ran Control-IQ 1.5 [14]. Tandem's t:slim X2 now runs Control-IQ+, and as of October 2026 Tandem lists Lyumjev U-100, NovoLog or Humalog as the insulins the pump and algorithm are indicated for; Fiasp is not on that list [15].

Reliability and Maintenance

Neither label sets a 48-hour site-change schedule. Both say infusion sets and insertion sites should be changed according to the pump maker's user manual [6][7]. What the labels do limit is how long the insulin itself stays in a pump reservoir: 6 days for Fiasp and 9 days for Lyumjev U-100, or the pump manual's limit if that is shorter [6][7]. Lilly's label explains that the reservoir limit is there to prevent insulin degradation and infusion set occlusion [7].

The trial data on clogging are mixed rather than alarming. In a 6-week pump study, no infusion-set occlusion was confirmed under the microscope with Fiasp or with standard aspart, yet 44% of Fiasp users changed a set early, against 16.7% on aspart [11]. When Lyumjev ran in the MiniMed 670G (an earlier system, since superseded by the 780G), overall unplanned set changes matched standard lispro, but set changes because of site reactions were more frequent with Lyumjev: 0.12 against 0 events per 30 days [12]. How often a given person should change sets is a question for the pump instructions and their care team.

Innovation and Future Directions

Insulin stability in pumps is an old problem. Insulin can clump into insoluble strands called fibrils, which can weaken the insulin and block delivery devices; commercial formulations rely on stabilizing ingredients to slow this [13]. Fiasp, for example, contains L-arginine, which Novo Nordisk added to keep the formulation stable [8]. Whether future fast formulations will cut fibrillation and catheter clogging further remains open, and as of October 2026 we had not found a published trial of a new formulation designed for that purpose.

Conclusion

Ultra-rapid insulins reach the blood faster, and in pooled AID trials that bought about one percentage point of time in range [2]. Some studies paid for it with more infusion-site reactions [7][10]. As of October 2026, the MiniMed 780G is FDA-approved for use with both Fiasp and Lyumjev [4], Tandem's t:slim X2 lists Lyumjev but not Fiasp [15], and for any pump both insulin labels point readers to the pump's user manual [6][7]. Whether the switch is worth it for one person is a decision to make with their care team.