What is the mechanism of action of GLP-1 (Glucagon-Like Peptide-1) agonists?

Mechanism of Action of GLP-1 Agonists

GLP-1 receptor agonists work primarily by binding to and activating GLP-1 receptors, stimulating glucose-dependent insulin secretion while inhibiting glucagon secretion, delaying gastric emptying, and reducing appetite through central nervous system effects. 1

Primary Mechanisms of Action

GLP-1 receptor agonists are modified peptides that share homology with endogenous GLP-1 but have been engineered to resist degradation by dipeptidyl peptidase-4 (DPP-4), extending their half-life significantly beyond the 1-2 minutes of native GLP-1. 1, 2, 3

Pancreatic Effects

• Insulin Secretion:

  • Stimulates insulin release from β-cells in a glucose-dependent manner
  • Activates GLP-1 receptors on β-cells, increasing intracellular cyclic AMP (cAMP) 3
  • Only triggers insulin secretion when blood glucose is elevated, explaining the low risk of hypoglycemia 1
  • May promote β-cell proliferation and protect against apoptosis 1

• Glucagon Suppression:

  • Inhibits glucagon secretion from pancreatic α-cells in a glucose-dependent manner 1
  • Only about 10-15% of α-cells express GLP-1 receptors 1
  • Suppression of glucagon helps reduce hepatic glucose production 1, 3

Gastrointestinal Effects

• Delayed Gastric Emptying:
  • Significantly slows gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone 1
  • Mediated primarily through vagal nerve pathways 1
  • GLP-1 receptors on the myenteric plexus activate nitrergic and cAMP pathways to inhibit vagal activity 1
  • This effect is more pronounced with short-acting GLP-1 agonists than long-acting ones due to tachyphylaxis 1
  • Patients who have had a vagotomy do not experience delayed gastric emptying with GLP-1 agonists 1

Central Nervous System Effects

• Appetite Regulation:
  • GLP-1 receptors in the hypothalamus and brainstem nuclei mediate appetite suppression and satiety 1
  • Reduces caloric intake and promotes weight loss 1
  • GLP-1 receptors are found in the hippocampus, neocortex, spinal cord, and cerebellum 1

Pharmacokinetic Modifications

Different GLP-1 receptor agonists have been modified to achieve varying durations of action:

• Short-acting agents (exenatide BID, lixisenatide):

  • Primarily reduce postprandial glucose through stronger effects on gastric emptying 4
  • Administered once or twice daily 4

• Long-acting agents (liraglutide, semaglutide, dulaglutide, exenatide weekly):

  • Greater effects on fasting glucose and HbA1c 4
  • Modifications include:
    • Albumin binding (semaglutide has greater albumin affinity than liraglutide) 1
    • Conjugation with immunoglobulin G fragments (dulaglutide) 1
    • Microsphere encapsulation for gradual release (long-acting exenatide) 1

Clinical Implications of Mechanism

• The glucose-dependent nature of insulin stimulation and glucagon suppression explains the low risk of hypoglycemia with these agents 1
• Delayed gastric emptying contributes significantly to postprandial glucose control 1
• Tachyphylaxis to the gastric emptying effect occurs with continuous exposure, particularly with long-acting agents 1
• The central effects on appetite contribute to the weight loss benefits seen with these medications 1

Important Considerations

• Short-acting GLP-1 agonists maintain their effect on gastric emptying during long-term treatment, while long-acting agents show diminished effects over time (tachyphylaxis) 4
• Semaglutide (a long-acting agent) has shown greater efficacy for both glucose lowering and weight reduction compared to other GLP-1 agonists 4
• The mechanism of action explains common side effects like nausea and vomiting, which are related to delayed gastric emptying 1

Understanding these mechanisms helps explain why GLP-1 receptor agonists are effective for both glycemic control and weight management, with additional benefits for cardiovascular and renal outcomes.