Efficacy and safety of Efsubaglutide Alfa in “overrun” patients in the SUPER2 trial: A post‐hoc analysis for comprehensive evaluation

Abstract Aims Efsubaglutide Alfa is a novel, long‐acting, once‐weekly GLP‐1 receptor agonist. In the pivotal phase 2b/3 SUPER2 trial, Efsubaglutide Alfa 3 mg plus metformin showed significant efficacy and favourable safety in patients with type 2 diabetes (T2D) inadequately controlled on metformin. This post‐hoc analysis evaluated the 1 mg dose. Materials and methods In phase 2b, patients with T2D on metformin were randomized (1:1:1) to once‐weekly Efsubaglutide Alfa 1 mg, 3 mg, or placebo for 12 weeks. After interim analysis, 3 mg was selected as the phase 3 dose. However, 155 patients already randomized (the “overrun” cohort) completed 24 weeks of double‐blind treatment with 1 mg, then entered 28 weeks of open‐label 3 mg and 4 weeks of follow‐up. This analysis focused on the 1 mg cohort. The primary endpoint was change in HbA1c at week 24; secondary endpoints included fasting plasma glucose (FPG), body weight, HbA1c <7.0%, and subgroup analyses. Results At week 24, HbA1c decreased by −1.69% (95% CI –1.91 to −1.47) with Efsubaglutide Alfa 1 mg versus −0.74% (−0.96 to −0.52) with placebo, a placebo‐corrected difference of −0.95% (95% CI –1.25 to −0.65; p < 0.0001). FPG decreased by −2.09 mmol/L versus −0.50 mmol/L with placebo (difference − 1.59 mmol/L; p < 0.001). Body weight reduction was modest and not significant (−2.8% vs. −1.3%; LSM −0.72 kg; p = 0.137). HbA1c <7.0% was achieved by 56.3% versus 11.1% with placebo ( p < 0.0001; odds ratio 8.3). Gastrointestinal adverse events were most common, generally mild and transient, and no drug‐related serious events occurred. Conclusions Efsubaglutide Alfa 1 mg provided clinically meaningful glucose lowering with good tolerability but without significant weight loss. These results support a lower‐dose strategy for elderly or frail patients, those with low BMI, or individuals sensitive to gastrointestinal effects, and as a possible lead‐in step before escalation. Confirmatory trials are warranted to establish long‐term outcomes.