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

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; I 2 =0.0%; p=0.2851; nine trials), ketoacidosis (RR 0.88, 95% CI 0.26 to 2.93; I 2 =0.0%; p=0.8593; two trials) and serious adverse events (RR 1.00, 95% CI 0.44 to 2.25; I 2 =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.