Regular human insulins versus rapid-acting insulin analogues in children and adolescents with type 1 diabetes: a systematic review with meta-analysis and trial sequential analysis.

Johanne Juul Petersen, Pascal Faltermeier, Sophie Juul, Caroline Barkholt Kamp, Christina Dam Bjerregaard Sillassen, Tiago Jeronimo Dos Santos, Janus Christian Jakobsen

Journal: BMJ open 2026;16(5):e100186

PMID: 42134835

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Abstract

OBJECTIVES

To assess the beneficial and harmful effects of regular human insulins versus rapid-acting insulin analogues in children and adolescents with type 1 diabetes.

DESIGN

Systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

DATA SOURCES

CENTRAL, MEDLINE, Embase, LILACS and other sources from inception to 30 January 2026.

STUDY SELECTION

Randomised clinical trials comparing regular human insulins versus rapid-acting insulin analogues (insulin aspart, lispro, glulisine) in children and adolescents with type 1 diabetes.

ANALYSES

Data were analysed using meta-analysis and trial sequential analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool, V.2, and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

PRIMARY OUTCOMES

Severe hypoglycaemia, ketoacidosis and serious adverse events.

RESULTS

10 trials randomising 1107 participants were included. The certainty of evidence was very low mainly due to high risk of bias and small sample sizes. Meta-analysis showed no evidence of a difference between regular human insulins and rapid-acting insulin analogues on severe hypoglycaemia (risk ratio (RR) 1.28, 95% CI 0.81 to 2.03; I²=0.0%; p=0.2851; nine trials), ketoacidosis (RR 0.88, 95% CI 0.26 to 2.93; I²=0.0%; p=0.8593; two trials) and serious adverse events (RR 1.00, 95% CI 0.44 to 2.25; I²=0.0%; p=0.9958; two trials). Trial sequential analysis showed that all meta-analyses of primary outcomes were underpowered.

CONCLUSIONS

Current research shows no differential effects between regular human insulins and rapid-acting insulin analogues for children and adolescents with type 1 diabetes, but the evidence is very uncertain.

PROSPERO REGISTRATION NUMBER

CRD42024508625.

Address: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark [email protected].; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.; Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.; Mental Health Services in the Capital Region of Denmark, Psykoterapeutisk Center Stolpegard, Gentofte, Denmark.; Department of Psychology, University of Copenhagen, Copenhagen, Denmark.; Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.; Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.; Department of Cardiology, Central and West Zealand Hospital, Slagelse, Denmark.; Unit of Pediatrics, Hospital Vithas Almería, Instituto Hispalense de Pediatría SL, Seville, Spain.; Department of Nursing Physiotherapy and Medicine, Faculty of Health Sciences, University of Almeria, Almería, Spain.; Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.; Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

DOI: 10.1136/bmjopen-2025-100186

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https://medlineplus.gov/diabetesmedicines.html

MeSH Terms: Humans, Diabetes Mellitus, Type 1, Child, Adolescent, Hypoglycemic Agents, Insulin, Short-Acting, Randomized Controlled Trials as Topic, Insulin, Regular, Human, Insulin, Insulin Aspart, Hypoglycemia, Insulin Lispro