This prospective cohort study investigated the longitudinal impact of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), on sarcopenia indicators and biomarkers of neuromuscular junction (NMJ) stability and neuronal health in older men with type 2 diabetes mellitus (T2DM), compared to sitagliptin as a control. Older adults with T2DM are at elevated risk for sarcopenia, characterized by loss of muscle mass, strength, and function, which can exacerbate disability and reduce quality of life.
The study enrolled 141 men aged 65 years or older (mean age ~70), divided into semaglutide (n=68) and sitagliptin (n=73) groups, with assessments at baseline, 6 months, and 1 year. Key outcomes included handgrip strength (HGS), gait speed, appendicular skeletal muscle mass index (ASMI) via bioelectrical impedance analysis, short physical performance battery (SPPB) scores, and plasma levels of C-terminal agrin fragment 22 (CAF22, a marker of NMJ degradation), neurofilament light chain (NfL, indicating neuronal injury), and brain-derived neurotrophic factor (BDNF, supporting neuronal health).
Results showed significant deteriorations in the semaglutide group: HGS decreased by 12.4% (P<0.001), gait speed by 10.2% (P=0.002), ASMI by 5.8% (P=0.012), and SPPB scores by 15.3% (P<0.001) over 12 months, compared to minimal changes in the sitagliptin group. Biomarker analysis revealed a 28.6% increase in CAF22 (P<0.001), 22.1% rise in NfL (P=0.003), and 18.4% reduction in BDNF (P=0.005) in semaglutide users, suggesting accelerated NMJ instability and neuronal damage. These changes correlated with physical declines (e.g., CAF22 inversely with HGS, r=-0.62, P<0.001). No significant differences were noted in glycemic control between groups, indicating the effects may be independent of glucose-lowering efficacy.
The discussion posits that semaglutide’s weight loss and metabolic effects might inadvertently promote muscle catabolism in frail older adults, potentially via reduced caloric intake or direct impacts on muscle innervation. Limitations include the observational design, male-only cohort, and lack of mechanistic insights. No competing interests were declared, and data are available upon request. The study underscores the need for musculoskeletal monitoring in semaglutide-treated older T2DM patients and calls for randomized trials to confirm these associations and explore interventions like exercise or NMJ-stabilizing agents.
Source: https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/bcp.70253?af=R
