Glucagon suppression under GLP-1RA therapy: hidden trade-offs for muscle and resilience

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have rapidly transformed the management of type 2 diabetes and obesity, with consistent benefits in weight reduction, glycaemic control, and cardiometabolic outcomes. Yet across trials, these agents are also associated with lean mass loss-a phenomenon insufficiently explained by reduced intake or muscle remodeling alone. Here, we propose that sustained glucagon suppression represents an overlooked systemic mechanism linking GLP-1RA therapy to progressive decline in muscle reserve. By impairing hepatic amino acid clearance and shifting substrate supply toward muscle proteolysis, chronic glucagon silencing may erode adaptive capacity and resilience, particularly in older adults, frail individuals, and those with multimorbidity. Viewed through the lens of exposure-related malnutrition, such drug-induced nutrient mismatch can be understood as iatrogenic undernutrition-metabolically silent at first, yet consequential for long-term muscle health and stress recovery. Recognition of this trade-off underscores the need for routine monitoring of muscle function and amino acid metabolism in long-term GLP-1RA users. Monitoring biomarker patterns and applying muscle-preserving strategies may help balance these benefits with long-term resilience.