Efficacy and safety of ultra‐rapid lispro versus lispro in children and adolescents with type 1 diabetes: The PRONTO‐Peds trial
Open accessAbstract
Aims: To evaluate the efficacy and safety of ultra‐rapid lispro (URLi) versus lispro in a paediatric population with type 1 diabetes (T1D) in a Phase 3, treat‐to‐target study. Materials and Methods: After a 4‐week lead‐in to optimize basal insulin, participants were randomized to double‐blind URLi ( n = 280) or lispro ( n = 298) injected 0 to 2 minutes prior to meals (mealtime), or open‐label URLi ( n = 138) injected up to 20 minutes after start of meals (postmeal). Participants remained on pre‐study basal insulin (degludec, detemir or glargine). The primary endpoint was glycated haemoglobin (HbA1c) change from baseline after 26 weeks (noninferiority margin 4.4 mmol/mol [0.4%]). Results: Both mealtime and postmeal URLi demonstrated noninferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi −0.23 mmol/mol (95% confidence interval [CI] −1.84, 1.39) and postmeal URLi −0.17 mmol/mol (95% CI −2.15, 1.81). Mealtime URLi reduced 1‐hour postprandial glucose (PPG) daily mean ( P = 0.001) and premeal to 1 hour postmeal PPG excursion daily mean ( P < 0.001) versus lispro. The rate and incidence of severe, nocturnal or documented hypoglycaemia (<3.0 mmol/L [54 mg/dL]) were similar for all treatments. With mealtime URLi versus lispro, the rate of postdose hypoglycaemia (<3.0 mmol/L) was higher at ≤2 hours ( P = 0.034). The incidence of treatment‐emergent adverse events was similar for all treatments. More participants reported an injection site reaction with mealtime URLi (7.9%) versus postmeal URLi (2.9%) and lispro (2.7%). Conclusions: In children and adolescents with T1D, URLi demonstrated good glycaemic control, and noninferiority to lispro in HbA1c change for mealtime and postmeal URLi. When dosed at the beginning of meals, URLi reduced 1‐hour PPG and PPG excursions versus lispro.
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This finding aligns with those of previous clinical trials that showed faster-acting insulins improve postprandial glucose without compromising overall glycaemic management or safety.
“This finding aligns with those of previous clinical trials that showed fasteracting insulins improve postprandial glucose without compromising overall glycaemic management or safety.80,81”
From The future of type 1 diabetes therapy (2025) · cites this paper as [81]
The Results (Efficacy) and Discussion report that mealtime ultra-rapid lispro improved postprandial glucose versus lispro while remaining noninferior for HbA1c in children and adolescents with type 1 diabetes. The Results (Safety) report similar overall rates of severe and documented hypoglycaemia, but higher early postdose hypoglycaemia and more injection-site reactions with mealtime ultra-rapid lispro. Thus, the unqualified claim that safety was not compromised overlooks reported safety differences. (LLM, conf=0.86)
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Cites
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“While the ISPAD guidelines recommend giving prandial insulin before meals, postmeal administration is acceptable in younger children who are at increased risk of hypoglycaemia due to unpredictable food intake and physical activity.(9) This study demonstrates that URLi can be administered after the meal if necessary wi…”
BackgroundMethod13. Children and Adolescents: <i>Standards of Medical Care in Diabetes—2021</i>
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Type 1 diabetes: A predictable disease
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MethodIncreasing Incidence of Type 1 Diabetes in Youth
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“Type 1 diabetes (T1D) is a major disease burden in children and adolescents,(1) and regional evidence suggests the incidence of T1D in youth is increasing.(2-4) As with adults, maintenance of tight glycaemic control is important to delay onset and slow the progression of diabetes-related complications.”
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“Other treat-totarget trials conducted in participants with T1D using MDI regimens with other rapid-acting insulins have also reported similar results.(16-19) Noninferiority of postmeal URLi to lispro for HbA1c change was also confirmed and there was no significant difference in HbA1c among the treatment groups after 2…”
ResultTreat-to-target trials: uses, interpretation and review of concepts
Garber, A. J. (2014) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12129 · Cited by 94 · cited 1× · see citing works
“Other treat-totarget trials conducted in participants with T1D using MDI regimens with other rapid-acting insulins have also reported similar results.(16-19) Noninferiority of postmeal URLi to lispro for HbA1c change was also confirmed and there was no significant difference in HbA1c among the treatment groups after 2…”
ResultKlaff, L. J., Cao, D., Dellva, M. A., Tobian, J. A., Miura, J., Dahl, D. B., Lucas, J., & Bue‐Valleskey, J. M. (2020) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14100 · Cited by 91 · cited 6× · see citing works
“This is consistent with the results of the PRONTO T1D study in adults.(14) Other treat-totarget trials conducted in participants with T1D using MDI regimens with other rapid-acting insulins have also reported similar results.”
BackgroundResultInfluentialSelf-citationUltrafast-Acting Insulins: State of the Art
Heinemann, L., & Muchmore, D. (2012) · Journal of Diabetes Science and Technology · doi:10.1177/193229681200600402 · Cited by 90 · cited 1× · see citing works
“There remains a need to continue to develop more rapid-acting insulin formulations with a time-action profile to better match that of endogenous insulin secretion to provide effective glycaemic control without risk of hypoglycaemia and hyperglycaemia.(11,12) Ultra-rapid lispro (URLi) is an insulin lispro formulation w…”
BackgroundBode, B. W., Iotova, V., Коваренко, М. А., Laffel, L. M., Rao, P. V., Deenadayalan, S., Ekelund, M., Larsen, S. F., & Danne, T. (2019) · Diabetes Care · doi:10.2337/dc19-0009 · Cited by 69 · cited 1× · see citing works
“Other treat-totarget trials conducted in participants with T1D using MDI regimens with other rapid-acting insulins have also reported similar results.(16-19) Noninferiority of postmeal URLi to lispro for HbA1c change was also confirmed and there was no significant difference in HbA1c among the treatment groups after 2…”
ResultSelf-citationMałecki, M., Cao, D., Liu, R., Hardy, T., Bode, B., Bergenstal, R., & Bue-Valleskey, J. (2020) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2020.0129 · Cited by 30 · cited 5× · see citing works
“In Phase 3 clinical trials, URLi has demonstrated noninferiority to lispro in glycated haemoglobin (HbA1c) change from baseline and superiority in PPG reduction in adults with T1D.(14,15)”
BackgroundInfluentialUndeniable Need for Ultrafast-Acting Insulin: The Pediatric Perspective
Cengiz, E. (2012) · Journal of Diabetes Science and Technology · doi:10.1177/193229681200600409 · Cited by 28 · cited 2× · see citing works
“needs as they get older and experience normal growth and development.(11) Advancements have been made in the treatment of T1D in youth, including the development of rapid-acting insulin analogues to”
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“In a pooled analysis comparing pharmacokinetics and pharmacodynamics between URLi and lispro following subcutaneous injection, URLi showed faster insulin lispro absorption, reduced late exposure, and overall shorter exposure duration compared with lispro.(13) In Phase 3 clinical trials, URLi has demonstrated noninferi…”
ResultInfluentialSelf-citation
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The future of type 1 diabetes therapy
Ziegler, A.-G., Cengiz, E., & Kay, T. W. H. (2025) · The Lancet · doi:10.1016/s0140-6736(25)01438-2 · Cited by 42 · see citing works
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“These study findings have recently been translated into a larger phase 3 treat-to-target study that evaluated the efficacy and safety of URLi versus Humalog in a paediatric population with T1D.(11) In children and adolescents with T1D, URLi showed a non-inferior glycated haemoglobin change, and a reduction in 1-h post…”
BackgroundMethodResultInfluentialSelf-citationThe Role of Ultra-Rapid-Acting Insulin Analogs in Diabetes: An Expert Consensus
Giorgino, F., Battelino, T., Bergenstal, R. M., Forst, T. M., Green, J. B., Mathieu, C., Rodbard, H. W., Schnell, O., & Wilmot, E. G. (2023) · Journal of Diabetes Science and Technology · doi:10.1177/19322968231204584 · Cited by 14 · see citing works
“Several trials reported a statistically significant higher rate of hypoglycemia within the first two hours after a meal, 14,15,22,23,27 but a statistically significant lower rate of late postprandial hypoglycemic episodes.”
InfluentialOptimal Prandial Timing of Insulin Bolus in Youths with Type 1 Diabetes: A Systematic Review
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“51 These trends were comparable to those observed with FAsp.”
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“[6,14] Two studies evaluated URLi vs. lispro use in insulin pumps in T1DM.”
Diagnostik, Therapie und Verlaufskontrolle des Typ-1-Diabetes mellitus im Kindes- und Jugendalter
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“…und kurzwirksames Humaninsulin zeigen bei Kindern Unterschiede bezüglich Wirkungsbeginn und Wirkdauer und sollten je nach Situation zur prandialen Substitution bei Kindern und Jugendlichen flexibel bei der konventionellen Insulintherapie, ICT mit Insulinpen, verwendet werden [32, 33, 34, 35].”
Preoperative Patient Evaluation
Villasenor, M., & Selzer, A. R. (2023) · Anesthesiology Clinics · doi:10.1016/j.anclin.2023.08.004 · Cited by 2 · see citing works
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Automatische Insulindosierung (AID)
Ware, J. (2024) · Die Diabetologie · doi:10.1007/s11428-024-01238-1 · Cited by 1 · see citing works
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Diagnostik, Therapie und Verlaufskontrolle des Diabetes mellitus im Kindes- und Jugendalter
Holder, M., Kamrath, C., Lange, K., Kummer, S., & Ziegler, R. (2026) · Die Diabetologie · doi:10.1007/s11428-026-01468-5
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“Although post-meal URLi administration was not inferior to pre-meal conventional RAA administration in terms of HbA1c levels, it is less effective at lowering blood glucose levels than pre-meal URLi administration [5,23].”
Diagnosis, Therapy and Follow-Up of Type 1 Diabetes Mellitus in Children and Adolescents
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“…insulin analogues and short-acting human insulin show differences in children in terms of onset and duration of action and, depending on the situation for prandial substitution in children and adolescents, should be used flexibly in conventional insulin therapy, ICT with insulin pens [32–35].”
Diagnostik, Therapie und Verlaufskontrolle des Diabetes mellitus Typ 1 im Kindes- und Jugendalter
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Role of Ultra-Rapid Acting Insulins in Management of Preschool Children with Type 1 Diabetes
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New Insulins, Biosimilars, and Insulin Therapy
Danne, T., Heinemann, L., & Pieber, T. (2024) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2024.2504
- Authors
- Wadwa, R. P., Laffel, L. M., Franco, D. R., Dellva, M. A., Knights, A. W., & Pollom, R. K.
- Affiliations
- University of Colorado Anschutz (US)
- Joslin Diabetes Center (US)
- CPCLIN/DASA Clinical Research Center São Paulo Brazil
- Eli Lilly (United States) (US)
- Corresponding author
- Pollom, Robyn K.
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2022-09-08
- Volume
- 25
- Issue
- 1
- Pages
- 89-97
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- PMC
- PMC10087819
- OpenAlex
- W4293013401
- Cited by
- 24
- References
- 22
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 2
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Obesity and Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- insulin lispro, type 1 diabetes, children and adolescents, HbA1c, non-inferiority, postprandial blood glucose, hypoglycemia, basal insulin, glycemic control, treatment-emergent adverse events, injection site reactions, insulin analogues, insulin degludec
- MeSH terms
- Adolescent, Child, Diabetes Mellitus, Type 1, Humans, Insulin, Insulin Lispro
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