Efficacy and safety of insulin icodec compared with insulin efsitora in patients with type 2 diabetes: a systematic review and network meta-analysis.

OBJECTIVE: We conducted this network meta-analysis to compare the efficacy and safety of insulin icodec vs insulin efsitora for patients with type 2 diabetes (T2D). METHODS: We conducted a comprehensive systematic search across PubMed, the Cochrane Library, and Embase up to November 11, 2025. Eligible trials compared insulin icodec and insulin efsitora against each other, placebo or other glucose-lowering drugs. Primary outcome was change in HbA1c. Secondary outcomes were change in body weight, percentage of patients achieving HbA1c < 7%, change in fasting plasma glucose (FPG), and safety outcomes including level 1 hypoglycemia, level 2 or level 3 hypoglycemia, adverse events (AEs), and serious adverse events (SAEs). We used version 2 of the Cochrane risk-of-bias tool to assess the risk of bias. A frequentist network meta-analysis was used to calculate the risk ratios or mean difference with corresponding 95% confidence intervals. RESULTS: Thirteen RCTs involving 7,402 participants were included. Insulin icodec resulted in a lower HbA1c level compared to insulin efsitora, but was associated with a higher incidence of level 1 hypoglycemia. The two treatments showed no significant differences in other outcomes, including change in body weight, percentage of patients achieving HbA1c <7%, change in FPG, incidence of level 2 or 3 hypoglycemia, AEs, and SAEs. Compared to daily insulins, insulin icodec led to lower HbA1c levels. Weight gain was lower with insulin glargine than with insulin icodec. A higher percentage of patients in the icodec group achieved HbA1c <7% compared to those receiving daily insulins. Regarding safety outcomes, insulin degludec had a lower incidence of both level 1 and level 2 or 3 hypoglycemia than the other three insulins. Insulin icodec showed a higher incidence of level 1 hypoglycemia than insulin glargine. Additionally, the incidence of AEs was higher with insulin icodec than with insulin degludec. CONCLUSIONS: In patients with T2D, once-weekly insulin icodec may provide slightly better glycaemic control than daily insulin. Insulin icodec was more effective than insulin efsitora in reducing HbA1c levels; however, this benefit was offset by a significantly higher risk of level 1 hypoglycemia. The two insulins were comparable in terms of body weight change, glycemic target achievement, FPG reduction, and safety profiles, including level 2 or 3 hypoglycemia, AEs, and SAEs. Direct head to head RCTs are warranted to confirm these findings. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251177019.