Comparative Effectiveness of Once-Weekly Insulin Efsitora Alfa in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials

BACKGROUND Achieving and maintaining a glycated hemoglobin (HbA1c) level <7% in patients with type 2 diabetes (T2D) remains challenging, partly because of the daily insulin injection burden. Insulin efsitora alfa is a long-acting insulin Fc–fusion protein designed for once-weekly administration, which may reduce injection burden. PURPOSE The purpose of this analysis is to evaluate the efficacy and safety of once-weekly insulin efsitora alfa compared with once-daily basal insulin in adults with T2D, stratified by baseline insulin use. DATA SOURCES PubMed, Web of Science, Scopus, and Cochrane CENTRAL were searched from inception through July 2025, along with ClinicalTrials.gov. STUDY SELECTION Randomized controlled trials (RCTs) enrolling adults with T2D that compared once-weekly insulin efsitora alfa with once-daily basal insulin for ≥12 weeks were included. Six trials met eligibility criteria. DATA EXTRACTION Two authors independently extracted data using a standardized form. The primary outcome was the mean change in HbA1c (%). Secondary outcomes included fasting plasma glucose, body weight, time in range, hypoglycemia, and adverse events. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. DATA SYNTHESIS Six RCTs, including 4,116 participants, were analyzed. Efsitora demonstrated HbA1c reduction comparable to daily basal insulin in insulin-treated patients (mean difference [MD] –0.06% [95% CI –0.24, 0.11]; P = 0.48) and insulin-naive patients (MD –0.03% [95% CI –0.12, 0.06]; P = 0.51). Nocturnal hypoglycemia episodes were fewer with efsitora in both insulin-treated patients (risk ratio [RR] 0.82 [95% CI 0.68, 0.98]; P = 0.03) and insulin-naive patients (RR 0.71 [95% CI 0.52, 0.95]; P = 0.02). LIMITATIONS All included trials were open-label, and follow-up duration was limited. Long-term outcomes, real-world adherence, and cost-effectiveness could not be fully assessed. CONCLUSIONS Once-weekly insulin efsitora alfa demonstrates glycemic control and overall safety comparable to once-daily basal insulin in adults with T2D, with fewer nocturnal hypoglycemia episodes. Longer-term RCTs and real-world studies are needed to define its long-term clinical and economic impact.