How do Glucagon-like peptide-1 (GLP-1) receptor agonists work?

Mechanism of Action of GLP-1 Receptor Agonists

GLP-1 receptor agonists work by activating GLP-1 receptors, which enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner, delays gastric emptying, and reduces food intake via central appetite suppression. 1

Primary Mechanisms of Action

• GLP-1 receptor agonists are analogs of the naturally occurring incretin hormone GLP-1, which is released by L-enteroendocrine cells in the terminal ileum and proximal colon in response to meals 2
• They selectively bind to and activate the GLP-1 receptor, a G-protein coupled receptor found primarily on pancreatic β cells 3
• Natural GLP-1 has a very short half-life of approximately 2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4), while GLP-1 receptor agonists are designed to resist this degradation 2, 4

Effects on Glucose Regulation

• GLP-1 receptor agonists stimulate insulin secretion from pancreatic β cells in a glucose-dependent manner, meaning insulin is only released when blood glucose levels are elevated 3
• They suppress glucagon secretion from pancreatic α cells, which reduces hepatic glucose production 2, 3
• The glucose-dependent nature of these actions explains the low risk of hypoglycemia with GLP-1 receptor agonists 2, 5
• GLP-1 receptor agonists may promote β cell proliferation and protect against apoptosis, potentially preserving pancreatic β cell mass 2

Gastrointestinal Effects

• GLP-1 receptor agonists delay gastric emptying through vagal nerve-mediated pathways 6
• This action reduces phasic gastric contractions, delays gastric emptying, reduces gastric acid secretion, and increases both fasting and postprandial gastric volumes 6, 2
• The delay in gastric emptying contributes significantly to the glucose-lowering effects by slowing nutrient absorption 6
• Short-acting GLP-1 receptor agonists (like exenatide) have more pronounced effects on delaying gastric emptying than long-acting formulations 6, 5
• Tachyphylaxis (diminishing response) occurs with continuous exposure, particularly with long-acting formulations 6, 2

Central Nervous System Effects

• GLP-1 receptor agonists reduce food intake via central appetite suppression 1, 7
• They act on GLP-1 receptors in the hypothalamus, which may be involved in the regulation of feeding behavior 7

Differences Between Short-Acting and Long-Acting Formulations

• Short-acting GLP-1 receptor agonists (exenatide b.i.d., lixisenatide) primarily reduce postprandial glucose by maintaining their effect on gastric emptying 5
• Long-acting GLP-1 receptor agonists (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, semaglutide) have more profound effects on fasting plasma glucose and HbA1c but develop tachyphylaxis to the gastric emptying effect 5

Clinical Considerations

• Common adverse effects include gastrointestinal symptoms (nausea, vomiting) that occur mainly during the initial stage of treatment and gradually diminish over time 1
• These medications should be used with caution in patients with pre-existing gastroparesis or delayed gastric emptying, as they may exacerbate symptoms 6
• Starting at low doses and titrating upward slowly can help minimize gastrointestinal side effects 6
• Beyond glucose control, GLP-1 receptor agonists have demonstrated cardiovascular benefits in patients with type 2 diabetes with a history of cardiovascular disease or risk factors 1, 5