Efficacy and Safety of Inhalational Insulin Compared With Rapid-Acting Insulin Analogs: A Systematic Review and Meta-Analysis

ABSTRACTS Purpose Technosphere insulin (TI) is an inhaled dry-powder insulin that has emerged as a potential alternative to subcutaneous rapid-acting insulin analogs (RAIA) for prandial glucose management. However, comprehensive evidence comparing TI with RAIA across both type 1 and type 2 diabetes mellitus remains limited. This systematic review and meta-analysis aim to compare the efficacy and safety of TI with RAIA. Methods A comprehensive search was done by using predefined keywords and Boolean operators in three databases (PubMed, Scopus, Embase). Studies comparing TI with RAIA were included. The quality of included studies was assessed using the JBI Critical Appraisal Checklist. A random-effects model was used to compare the mean difference (MD) in HbA1c. Heterogeneity was assessed using I² statistics, and publication bias was evaluated using funnel plots. Hypoglycaemia, weight change, and pulmonary safety were synthesized narratively due to heterogeneous outcome definitions. Findings Six trials with a total of 1295 participants were included. No statistically significant difference in HbA1c reduction was observed between TI and RAIA (MD: −0.09; 95% confidence interval: −0.24 to 0.07; P = 0.28; I² = 35%). In subgroup analyses, neither TI versus RAIA alone nor TI plus basal insulin versus RAIA plus basal insulin showed a statistically significant difference in HbA1c reduction. Narrative synthesis indicated lower hypoglycaemia rates and weight neutrality or modest weight benefit with TI. Cough, though mild and transient, was the most common adverse event, and pulmonary changes were small and reversible. Implications TI provides comparable glycaemic control to RAIA, with no evidence of superior efficacy in HbA1c reduction. Therefore, the clinical value of inhaled insulin may depend less on glycaemic control and more on its role as a patient-preferred, noninvasive alternative offering a distinct risk-benefit balance, potentially enhancing adherence and quality of life in selected individuals. Limitations include the small number of eligible trials and heterogenous safety outcome reporting. Future research should prioritize long-term pulmonary safety.