What is the mechanism of action of GLP-1 (Glucagon-Like Peptide-1) agonists, such as liraglutide (Victoza), semaglutide (Ozempic), and dulaglutide (Trulicity)?

Mechanism of Action of GLP-1 Agonists

GLP-1 receptor agonists work primarily by activating the GLP-1 receptor, which increases intracellular cyclic AMP (cAMP) in pancreatic beta cells, leading to glucose-dependent insulin release while decreasing glucagon secretion and slowing gastric emptying. 1, 2

Primary Mechanisms

GLP-1 receptor agonists have multiple complementary mechanisms of action:

1. Pancreatic Effects:

   • Insulin secretion: Stimulate glucose-dependent insulin release from pancreatic beta cells 3
   • Glucagon suppression: Decrease glucagon secretion in a glucose-dependent manner 1
   • First- and second-phase insulin secretion: Both phases are enhanced compared to placebo 2

2. Gastrointestinal Effects:

   • Delayed gastric emptying: Slow the rate at which food leaves the stomach 3
   • Reduced postprandial glucose: Particularly prominent with short-acting GLP-1 agonists 4

3. Central Nervous System Effects:

   • Appetite regulation: Act on receptors in the hypothalamus and brainstem to reduce hunger 3
   • Increased satiety: Promote feelings of fullness, contributing to reduced caloric intake 3

Molecular Mechanism

At the molecular level, GLP-1 receptor agonists:

• Bind to the GLP-1 receptor, a membrane-bound cell-surface receptor 1, 2
• Activate the receptor, which is coupled to adenylyl cyclase by stimulatory G-protein (Gs) 1
• Increase intracellular cyclic AMP (cAMP) levels in beta cells 1, 2
• Trigger downstream signaling cascades that ultimately lead to insulin vesicle exocytosis 1

Differences Between Short-Acting and Long-Acting GLP-1 Agonists

The GLP-1 receptor agonist class includes both short-acting and long-acting agents with distinct pharmacodynamic profiles:

• Short-acting agents (exenatide twice-daily, lixisenatide):

  • Primarily reduce postprandial glucose by delaying gastric emptying
  • Have less effect on fasting plasma glucose
  • Maintain their effect on gastric emptying during long-term treatment 5, 4

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

  • Have more profound effects on fasting plasma glucose and HbA1c
  • Show tachyphylaxis (diminishing effect over time) regarding gastric emptying
  • Provide more stable drug concentrations in plasma 5, 4

Structural Considerations

GLP-1 receptor agonists vary in their structural design:

• Liraglutide: An acylated human GLP-1 analog with 97% amino acid sequence homology to endogenous human GLP-1(7-37) 1
• Dulaglutide: A fusion protein consisting of two identical, disulfide-linked chains containing GLP-1 analog sequences linked to modified human immunoglobulin G4 (IgG4) 2
• Semaglutide: A liraglutide analog with greater albumin affinity 6
• Tirzepatide: A novel dual GIP/GLP-1 receptor agonist that activates both GLP-1 and GIP receptors 6

Clinical Implications of the Mechanism

The unique mechanism of action of GLP-1 receptor agonists results in several clinical advantages:

• Low hypoglycemia risk: The glucose-dependent nature of insulin secretion and glucagon suppression minimizes hypoglycemia risk 3
• Weight loss effects: Central effects on appetite combined with delayed gastric emptying contribute to weight reduction 3
• Cardiovascular benefits: GLP-1 receptors in the cardiovascular system may contribute to the cardioprotective effects seen with these agents 3

Potential Limitations and Side Effects

The mechanism of action also explains common side effects:

• Gastrointestinal effects: Nausea, vomiting, and diarrhea result from delayed gastric emptying 3
• Reduced effectiveness in gastroparesis: Pre-existing delayed gastric emptying may limit efficacy and increase side effects 2

Understanding the complex mechanism of action of GLP-1 receptor agonists helps explain their multifaceted benefits in glycemic control, weight management, and cardiovascular risk reduction in patients with type 2 diabetes and obesity.