Sex specific responses to oral vs. subcutaneous semaglutide in type 2 diabetes mellitus: A 12-month real-world study

Background and aim: Semaglutide therapy improves glycaemic control, weight loss, and cardiovascular risk reduction in patients with type 2 diabetes mellitus (T2D). Sex-specific differences in the response to oral versus subcutaneous formulation remain unexplored in real-world settings. This interventional pilot study compares the 12-month effectiveness of oral and subcutaneous semaglutide in a real-world cohort of T2D patients, with focus to sex-based differences in treatment outcomes. Methods and results: Two-hundred and twelve T2D patients, equally assigned to oral or subcutaneous semaglutide (n = 106 per group), were enrolled. The primary endpoint was the change in HbA1c. Secondary endpoints included variations in anthropometric and metabolic parameters, analysed both in the overall cohort and through a sex-stratified approach. Two-hundred and eight patients completed the study. In men, subcutaneous semaglutide resulted in significant reductions in delta(Δ)_weight (p = 0.010), Δ_HbA1c (p = 0.037), and Δ_LDL (p = 0.038) compared to the oral formulation. In women, subcutaneous semaglutide led to significantly lower Δ_hepatic steatosis index (p = 0.024). Additionally, women treated with subcutaneous semaglutide showed a significantly greater reduction in Δ_GOT (p = 0.035) compared to men. Conclusions: This real-world study suggests that subcutaneous semaglutide provides greater metabolic benefits than the oral formulation, particularly in men. Women treated with subcutaneous semaglutide experience more favorable liver responses, emphasizing the personalization of T2D treatment.