Effects of Glucagon-Like Peptide-1 Receptor Agonists on Hypothalamic-Pituitary-Adrenal Axis in Healthy Volunteers

Context: Recent findings from animal and human studies indicate that glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) modulate stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis, which may have relevant clinical implications. Objective: To investigate the influence of GLP-1 RA treatment on HPA axis activity compared with placebo in healthy volunteers. Design: Double-blind, randomized, crossover study. Setting: University Hospital Basel, Switzerland. Participants: Twenty healthy volunteers. Intervention: Dulaglutide (Trulicity (R)) 1.5 mg and placebo (0.9% sodium chloride) were given subcutaneously once weekly for 3 weeks. Main Outcome Measures: Twenty-four-hour urinary free cortisol, circadian rhythm of serum and salivary cortisol, cortisol after 1 mg dexamethasone suppression test, and cortisol levels before and after stimulation with ACTH. Results: Urinary free cortisol levels were similar under dulaglutide [median (interquartile range) 240 nmol/L (164, 324)] vs placebo [188 nmol/L (133, 338), P = 0.131]. The circadian rhythm of serum and salivary cortisol were comparable in both groups as were cortisol levels after dexamethasone [dulaglutide 28 nmol/L (22, 47.5) vs placebo 26.5 nmol/L (15.8, 45.5), P = 0.4]. Serum cortisol levels in dulaglutide and placebo treated participants were 522 nmol (388, 710) and 530 nmol/L (394, 747), before (P = 0.6), and 658 nmol/L (604, 810) and 636 nmol/L (512, 910) after ACTH stimulation (P = 0.87). Conclusion: Our results suggest that there is no activation of the HPA axis by long-term GLP-1 RA exposure, particularly dulaglutide, at the medically approved dosage of 1.5 mg once weekly.