Semaglutide use is associated with neuromuscular junction degradation in older adults with type II diabetes mellitus

Aims Older men with type 2 diabetes mellitus (T2DM) face a heightened risk of sarcopenia. This study aimed to compare the longitudinal effects of semaglutide, a glucagon‐like peptide‐1 receptor agonist and sitagliptin as the control group on sarcopenia indicators and biomarkers of neuromuscular junction and neuronal health in patients with T2DM over 1 year. Methods A cohort of 141 older men with T2DM (semaglutide, n = 68; sitagliptin group, n = 73) underwent assessments at baseline, 6 months and 1 year. Measured parameters included handgrip strength (HGS), gait speed, appendicular skeletal muscle mass index (ASMI), short physical performance battery (SPPB) and plasma concentrations of C‐terminal agrin fragment 22 (CAF22), neurofilament light chain (NfL) and brain‐derived neurotrophic factor (BDNF). Results Over the study period, the semaglutide group exhibited significant reductions in HGS, gait speed, ASMI and SPPB scores (all P < .05). Concurrently, this group exhibited more pronounced elevation of plasma CAF22 and NfL levels compared to the sitagliptin group (all P < .05). Among the patients taking semaglutide, higher CAF22 and NfL levels generally correlated with poorer HGS, ASMI and SPPB scores. In contrast, lower BDNF levels were associated with reduced ASMI and SPPB at specific time points (all P < .05). Multiple regression analysis confirmed significant negative associations between CAF22 and NfL, and a positive association between BDNF and sarcopenia parameters, specifically among patients taking semaglutide. Conclusions Semaglutide treatment in older men with T2DM may be associated with a decline in muscle strength and physical performance, potentially associated with neuromuscular junction degradation and neuronal damage. These findings underscore the importance of closely monitoring musculoskeletal health in patients receiving semaglutide.