Computational modelling the impact of GLP-1 receptor agonists on botulinum toxin A: Evidence for reduced treatment durability across neurologic and aesthetic indications

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed metabolic and aesthetic medicine, yet their potential influence on botulinum toxin type A (BoNT-A) pharmacodynamics remains unexplored. Using the AesthetiSIM™ microsimulation platform, a transparent, parameterized in-silico model was developed to estimate whether GLP-1-related changes in metabolism and neuromuscular recovery could alter toxin durability. Twenty-five thousand virtual patients were generated, representing two domains of BoNT-A use: chronic migraine (n = 20,000) and masseter prominence (n = 5000). Virtual subjects were randomly assigned to semaglutide, tirzepatide, liraglutide, dulaglutide, or control conditions, and simulated over one year under standardized 100-unit BoNT-A dosing. The framework incorporated three mechanistic domains-synaptic modulation via cAMP-PKA-mediated SNAP-25 phosphorylation, lean-mass reduction affecting diffusion kinetics, and systemic metabolic variability reflecting diabetic or rapid-weight-loss phenotypes. In chronic migraine, mean BoNT-A duration declined from 14.0 ± 2.3 weeks in controls to 12.6, 12.5, 12.2, and 11.8 weeks across GLP-1 exposures (all p < 0.001; hazard ratio range 1.54-1.95). In masseter prominence, mean duration decreased from 20.1 ± 2.9 weeks to 17.3, 17.0, 16.7, and 16.2 weeks, with hazard ratios 1.72-2.08. Early wear-off and uncovered symptomatic periods rose proportionally across agents, with the hierarchy tirzepatide > liraglutide > dulaglutide > semaglutide. Sensitivity analyses indicated that approximately 55 % of the reduction in duration was attributable to synaptic modulation, 30 % to lean-mass decline, and 15 % to metabolic variability. These findings suggest a biologically plausible interaction between GLP-1 signalling and BoNT-A recovery dynamics. The results are exploratory and derive entirely from computational modelling rather than clinical observation. Experimental validation-such as neuronal culture assays or prospective patient cohorts-is required before any modification of treatment intervals or dosing practices can be considered.

Keywords: Aesthetic medicine; Botulinum toxin type A; Chronic migraine; GLP-1 receptor agonists; Pharmacodynamics; SNAP-25.