What is the mechanism of action of retatrutide (glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist)?

Mechanism of Action of Retatrutide

Retatrutide is a novel triple-hormone receptor agonist that simultaneously activates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors, producing potent metabolic effects through multiple complementary pathways.

Receptor Activation Profile

Retatrutide works by binding to and activating three key metabolic hormone receptors:

• GLP-1 receptor: Activates G-protein coupled receptors that increase intracellular calcium in pancreatic β-cells 1
• GIP receptor: Binds with high affinity to GIP receptors 1
• Glucagon receptor: Unique addition compared to dual agonists like tirzepatide 2

This triple-receptor activation creates synergistic effects that exceed those of single GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists.

Pancreatic Effects

Retatrutide exerts several important effects on pancreatic function:

• Enhanced insulin secretion: Stimulates glucose-dependent insulin release from β-cells 3
• Glucagon regulation:
  • Inhibits glucagon secretion during hyperglycemia via GLP-1 receptor activation 1
  • Permits appropriate glucagon secretion during euglycemia or hypoglycemia via GIP receptor activation 1
• β-cell protection: May promote β-cell proliferation and protect against apoptosis 1, 3

Gastrointestinal Effects

Retatrutide significantly influences gastrointestinal function:

• Delayed gastric emptying: Inhibits gastric peristalsis while increasing pyloric tone 1
• Reduced gastric acid secretion: Decreases acid production 1
• Increased gastric volumes: Both fasting and postprandial 1

These effects are mediated primarily through vagal nerve pathways, with GLP-1 receptors on the myenteric plexus activating nitrergic and cyclic adenosine monophosphate pathways to inhibit vagal activity 1.

Central Nervous System Effects

Retatrutide acts on receptors in key brain regions:

• Hypothalamus and brainstem: Activates GLP-1 and GIP receptors to regulate appetite, satiety, and energy intake 3
• Arcuate nucleus: Mediates appetite suppression 3
• Area postrema and nucleus tractus solitarius: Influences satiety signals 3

Metabolic Effects

The combined receptor activation produces profound metabolic effects:

• Body composition changes: Significantly reduces total body fat mass (up to 26.1% reduction with 8mg dose) 4
• Weight reduction: Produces substantial weight loss (up to 24.2% at 48 weeks with 12mg dose) 5
• Glycemic control: Improves HbA1c levels in a dose-dependent manner 6

Pharmacokinetic Considerations

Like other GLP-1 receptor agonists, retatrutide has been molecularly modified to:

• Resist enzymatic degradation: Prevents rapid inactivation by dipeptidyl peptidase-4 1
• Support weekly dosing: Pharmacokinetics allow for once-weekly administration 2

Clinical Implications

The triple-receptor mechanism of retatrutide explains several important clinical observations:

• Minimal hypoglycemia risk: Due to glucose-dependent insulin secretion 1
• Dose-dependent effects: Higher doses produce greater metabolic benefits 5
• Gastrointestinal side effects: Common adverse events include nausea, diarrhea, and vomiting 6, 5

The unique addition of glucagon receptor activation alongside GLP-1 and GIP receptor stimulation appears to enhance weight loss beyond what is achieved with single or dual agonists, though the exact contribution of glucagon receptor activation requires further clarification 2.