Aims <p>Once-weekly novel insulin preparations such as Icodec and basal insulin Fc (BIF)/insulin Efsitora Alfa have raised hope among clinicians and patients when they were developed and evaluated in a series of clinical trials. However, there were conflicting results regarding their efficacy and safety. This meta-analysis was carried out to evaluate the efficacy and safety of once-weekly insulin in patients with Type 2 diabetes mellitus (T2DM).</p> Methods <p>PubMed/MEDLINE, Cochrane database, Scopus, and WHO International Clinical Trials Registry Platform (ICTRP) were searched till November 2024 for randomized controlled trials (RCTs). Our literature search found 2759 articles, out of which 11 studies with 11 reports were included in the meta-analysis as per eligibility criteria.</p> Results <p>5799 participants from 11 RCTs were included. Once-weekly insulin showed significant reduction of HbA1c, and pooled mean difference of once-weekly insulin vs once-daily insulin was – 0.09 (95% CI – 0.16 to – 0.02). Subgroup analysis revealed that Icodec – 0.12 (95% CI – 0.20 to – 0.04) was found to be superior, whereas BIF was found to be non-inferior 0.01 (95% CI – 0.11 to 0.13) compared to once-daily insulin regimen in reduction of HbA1c in T2DM. No significant differences were observed between once-weekly and once-daily insulin for other safety outcomes.</p> Conclusions <p>Once-weekly insulin regimen was superior in reducing HbA1c level while maintaining a similar safety profile to the once-daily insulin regimen, thus suggesting that such regimen may potentially be an alternative to the currently established once-daily basal insulin regimen.</p> Graphical abstract <p></p>