Efficacy and safety of once-weekly IcoSema compared to active comparators in adults with type 2 diabetes: A systematic review and comparator-stratified quantitative synthesis of randomized controlled trials

IcoSema, a once-weekly fixed-ratio combination of insulin icodec and semaglutide, aims to simplify treatment and improve outcomes in adults with type 2 diabetes. While individual phase 3 trials have demonstrated its benefits compared to insulin icodec, semaglutide, and basal–bolus insulin regimens, a comprehensive synthesis is lacking.

To evaluate the efficacy and safety of once-weekly IcoSema compared to active comparators through a systematic review and comparator-stratified, study-level quantitative synthesis of available phase 3 randomized controlled trials.

We performed a systematic review with comparator-stratified, study-level quantitative analyses of three phase 3 randomized controlled trials (COMBINE 1-3), including 2653 adults with type 2 diabetes. Outcomes assessed were changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), time in range (TIR), body weight, and rates of level 2/3 hypoglycemia. Data synthesis was by comparator group to address clinical heterogeneity.

Compared with insulin icodec, IcoSema significantly improved glycemic control (HbA1c MD: −0.70%), increased TIR (+14%), and resulted in substantial weight loss (−5.67 kg), while markedly reducing hypoglycemia risk (RR 0.34). Compared to semaglutide, IcoSema reduced HbA1c by 0.54% and lowered FPG, but caused a 4.66 kg weight gain with no significant difference in hypoglycemia. Compared to basal–bolus therapy, IcoSema showed similar glycemic efficacy (HbA1c MD: −0.07%), significant weight loss (−6.72 kg), and greatly decreased hypoglycemia risk (RR 0.17). Gastrointestinal adverse events were more common versus insulin icodec but similar to other comparators. No consistent increase in serious adverse events or discontinuations was noted.

Once-weekly IcoSema offers superior or comparable glycemic efficacy, weight benefits, and reduced hypoglycemia compared to standard therapies in type 2 diabetes, with a safety profile consistent with GLP-1 RA/basal insulin combinations. Its simplified dosing may improve adherence and clinical outcomes.