What is the effect of Glucagon-like peptide-1 (GLP-1) inhibitors on the Hypothalamic-Pituitary-Adrenal (HPA) axis?

From the Guidelines

GLP-1 inhibitors have a modulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis, potentially reducing its activity, although the provided evidence focuses on GLP-1 receptor agonists, not inhibitors. The evidence from studies such as the LEADER trial 1 and the SUSTAIN-6 trial 1 demonstrates the cardiovascular benefits of GLP-1 receptor agonists like liraglutide and semaglutide, but does not directly address the impact on the HPA axis. However, based on the known effects of GLP-1 receptor agonists, which are closely related to GLP-1 inhibitors, these medications may decrease cortisol levels and blunt stress-induced HPA axis activation by inhibiting corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion. Some key points to consider include:

• The mechanism of GLP-1 receptor agonists involves GLP-1 receptors in the hypothalamus and pituitary gland.
• The HPA axis effects might partially explain improvements in conditions associated with HPA axis dysregulation, such as obesity, metabolic syndrome, and certain mood disorders.
• The clinical significance of these effects varies between individuals, and they typically don't cause adrenal insufficiency at standard therapeutic doses.
• Patients with pre-existing adrenal conditions should be monitored more closely when starting these medications, although this guidance is based on the use of GLP-1 receptor agonists. Given the focus of the provided evidence on GLP-1 receptor agonists rather than inhibitors, and considering the need for caution in real-life clinical medicine, it is reasonable to approach the use of GLP-1 inhibitors with consideration of their potential impact on the HPA axis, similar to that of GLP-1 receptor agonists, but with careful monitoring and management of patients with pre-existing adrenal conditions.

From the Research

Impact of GLP-1 Inhibitors on the HPA Axis

• The provided studies do not directly address the impact of GLP-1 inhibitors on the Hypothalamic-Pituitary-Adrenal (HPA) axis 2, 3, 4, 5, 6.
• The studies focus on the effects of GLP-1 receptor agonists on type 2 diabetes, obesity, and cardiovascular outcomes, but do not mention the HPA axis.
• Therefore, there is no direct evidence from the provided studies to determine the impact of GLP-1 inhibitors on the HPA axis.

Related Effects of GLP-1 Receptor Agonists

• GLP-1 receptor agonists have been shown to have various effects on the body, including:
  • Improving glycemic control and reducing body weight 2, 3, 4, 5, 6
  • Reducing cardiovascular risk factors and improving cardiovascular outcomes 2, 3, 6
  • Having potential benefits for the treatment of obesity and non-alcoholic fatty liver disease 4, 6
• However, these effects do not provide direct insight into the impact of GLP-1 inhibitors on the HPA axis.

Limitations of the Provided Studies

• The provided studies do not investigate the specific effects of GLP-1 inhibitors on the HPA axis.
• Further research is needed to determine the impact of GLP-1 inhibitors on the HPA axis, as the current evidence does not provide a clear answer to this question 2, 3, 4, 5, 6.