Mechanism of Action of Tirzepatide
Tirzepatide is a dual GIP/GLP-1 receptor co-agonist that works by activating both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors to improve glycemic control and reduce body weight. 1
Primary Mechanism Components
Receptor Binding Profile
- Binds to the GIP receptor with high affinity
- Has approximately 5 times less affinity for the GLP-1 receptor compared to endogenous GLP-1 1
- Functions as a unimolecular dual agonist engineered as an acylated synthetic peptide 2
- Molecular modifications allow binding to albumin, enabling once-weekly dosing 3
Pancreatic Effects
GLP-1 receptor activation:
- Increases intracellular calcium in β-cells leading to insulin exocytosis
- Inhibits glucagon secretion from α-cells in hyperglycemic conditions
- May promote β-cell proliferation and protect against apoptosis 1
GIP receptor activation:
- Stimulates glucose-dependent insulin secretion
- Augments glucagon secretion during euglycemia/hypoglycemia
- Inhibits glucagon secretion during hyperglycemia 1
Gastrointestinal Effects
- Delays gastric emptying primarily through GLP-1 receptor activation
- Inhibits gastric peristalsis while increasing pyloric tone
- Mediated by vagus nerve pathways 1
- Reduces gastric acid secretion
- Increases fasting and postprandial gastric volumes 1
Central Nervous System Effects
- Both GIP and GLP-1 receptors are located in:
- Hypothalamus
- Brainstem nuclei (area postrema and nucleus tractus solitarius)
- These regions regulate appetite, satiety, and energy expenditure 1
- GLP-1 receptors are also found in the hippocampus, neocortex, spinal cord, and cerebellum 1
- Suppresses the arcuate nucleus and induces meal termination in parabrachial neurons 1
Clinical Differentiation from GLP-1 RAs
- Produces greater reductions in HbA1c and body weight compared to selective GLP-1 receptor agonists like semaglutide and dulaglutide 1, 2
- Improves insulin sensitivity and insulin secretory responses to a greater extent than semaglutide 2
- Associated with lower prandial insulin and glucagon concentrations 2
- Causes similar reductions in appetite as GLP-1 RAs but greater weight loss 2
Pharmacokinetic Considerations
- Modified to prevent rapid inactivation by dipeptidyl peptidase-4 1
- Acylation technology enables binding to albumin, extending half-life for once-weekly dosing 3
Important Clinical Nuances
- The exact contribution of GIP receptor activation to tirzepatide's effects remains somewhat uncertain 4
- In vitro studies suggest tirzepatide may have a biased GLP-1 receptor activation profile and cause GIP receptor downregulation 4
- Unlike other GLP-1 RAs, tirzepatide appears to have greater effects on metabolic parameters, which may be attributed to its dual receptor activity 3
- The glucose-lowering effects of tirzepatide are glucose-dependent, explaining the low risk of hypoglycemia 1
Cardiovascular Effects
- GLP-1 receptors are primarily localized to the sinoatrial node and arterial walls 1
- Cardioprotective effects may include:
- Improved myocardial substrate utilization
- Anti-inflammatory and anti-atherosclerotic effects
- Reduced myocardial ischemia injury
- Lower systemic and pulmonary vascular resistance
- Improved lipid profiles 1
The unique dual receptor targeting mechanism of tirzepatide represents a significant advancement in incretin-based therapies, offering superior glycemic control and weight reduction compared to selective GLP-1 receptor agonists.