The GLP-1 Receptor Agonist with Triple Mechanism of Action
Based on the available evidence, there is no GLP-1 receptor agonist with a true "triple mechanism of action" in the traditional sense. However, the question likely refers to tirzepatide, which is technically a dual GIP/GLP-1 receptor agonist (not a pure GLP-1 agonist) that activates two distinct receptor pathways 1.
Understanding Tirzepatide's Mechanism
Tirzepatide is a dual GIP/GLP-1 receptor agonist that binds to both glucose-dependent insulinotropic polypeptide (GIP) receptors and GLP-1 receptors, though its affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1 1.
Key Mechanistic Actions:
GLP-1 receptor activation stimulates insulin secretion from pancreatic β cells, inhibits glucagon secretion, delays gastric emptying, and reduces appetite through central nervous system pathways 1
GIP receptor activation augments insulin secretion and modulates glucagon secretion in a glucose-dependent manner (inhibits in hyperglycemia, augments in euglycemia/hypoglycemia) 1
Combined receptor activation produces synergistic effects on appetite regulation through hypothalamic and brainstem nuclei that mediate satiety, energy intake, and expenditure 1
Clinical Superiority of Tirzepatide
Tirzepatide produced greater reductions in HbA1c and body weight compared with semaglutide and dulaglutide 1:
- Mean weight loss of 15% at 72 weeks in non-diabetic obese patients 1
- Weight reductions up to 20.9% at higher doses (15 mg) 1
- This degree of weight loss previously was only reported with bariatric surgery 1
Important Clinical Distinction
While tirzepatide has dual receptor agonism (which could be considered "two mechanisms"), the question about a "triple mechanism" may be a misconception. Traditional GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) work through multiple downstream effects but activate only one receptor type 1, 2.
Standard GLP-1 Receptor Agonist Effects Include:
- Glucose-dependent insulin secretion enhancement 1, 2
- Glucagon suppression at hyper/euglycemia 1, 2
- Delayed gastric emptying 1
- Central appetite suppression 1
- Cardiovascular protection through multiple pathways 3
If seeking the most potent weight loss and glycemic control agent in this class, tirzepatide is the answer 1.