Abstract
Background Symptoms of adrenal insufficiency (AI) are often nonspecific, hence can complicate or delay its diagnosis. The insulin tolerance test (ITT) remains the gold standard for diagnosing secondary and tertiary AI, but is elaborate, uncomfortable and carries risks for patients due to insulin-induced hypoglycemia. Consequently, there is need for a safe, feasible oral test capable of accurately assessing the entire hypothalamic–pituitary–adrenal (HPA) axis. Limited evidence indicates that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can activate the HPA axis in rodents and humans. However, the effects of orally administered GLP-1 RAs, such as semaglutide, on the HPA axis have not yet been investigated. Patients and Methods In this randomized, placebo-controlled, double-blind, cross-over study we investigated the acute effect of a single dose 14mg oral semaglutide vs placebo on the HPA axis. During both study visits, blood and saliva samples were drawn every 15-30 minutes until 210 minutes for measurements of serum cortisol, adrenocorticotropic hormone (ACTH) and salivary cortisol levels. Delta values for each time point were calculated (eg delta serum cortisolΔ30min = serum cortisol30min—serum cortisolbaseline). Results Twenty male healthy volunteers were included. Median age was 27 years (IQR 24, 31) and mean body mass index 24.5 kg/m2 (SD ±2.3). Mean baseline serum cortisol values were similar in the semaglutide group with 394 nmol/L (± 81) and the placebo group with 371 nmol/L (±75), P = .17. Mean delta serum cortisol levels were significantly higher at 75 min after oral semaglutide (delta serum cortisol −34.6 nmol/L (+120)) vs placebo (−103.5 nmol/L (+76)), P = .02, and this effect was even more pronounced at 90 min and 120 min. Delta salivary cortisol was higher at 120 min after semaglutide (0.2 nmol/L (+9.8)) vs placebo (−5.6 nmol/L (+4.7), P = .04). In parallel, delta median ACTH was higher after semaglutide at 75 min and 90 min with a maximal effect at 90 min (6.95 pmol/L (IQR) (−0.98; 12.15) vs placebo −3.65 pmol/L (−6.35; 0.08), P = .01. Conclusions Oral semaglutide can stimulate serum cortisol, salivary cortisol and ACTH in healthy men, and may therefore be evaluated as a novel oral stimulation test for the entire HPA axis in assessing for AI. Possible mechanisms could include co-stimulation due to the anatomical proximity of hypothalamic GLP-1 receptors to corticotropin releasing hormone producing neurons and a relative blood glucose-lowering effect of oral semaglutide.