What is the mode of action for Zepbound (tirzepatide)?

Mechanism of Action of Zepbound (Tirzepatide)

Dual Receptor Agonism

Zepbound (tirzepatide) is a first-in-class dual agonist that activates both glucose-dependent insulinotropic polypeptide (GIP) receptors and glucagon-like peptide-1 (GLP-1) receptors, representing a fundamentally different mechanism than single-receptor GLP-1 agonists. 1, 2

• Tirzepatide is an acylated peptide engineered to simultaneously activate both GIP and GLP-1 receptors, which are key mediators of insulin secretion and are also expressed in brain regions that regulate food intake 3
• The dual-receptor action provides enhanced metabolic benefits, including delayed gastric emptying, suppressed appetite, and improved insulin secretion, compared to semaglutide's single-receptor action 2

Glucose Regulation Mechanisms

• Tirzepatide stimulates glucose-dependent insulin secretion from pancreatic β-cells, meaning insulin release only occurs when blood glucose is elevated, minimizing hypoglycemia risk 1, 3
• The medication reduces inappropriate glucagon secretion, helping to prevent hepatic glucose production particularly in patients with type 2 diabetes 2
• Both insulin stimulation and glucagon suppression are glucose-dependent, explaining the minimal risk for hypoglycemia when used as monotherapy 1, 2
• Tirzepatide may promote β-cell proliferation and protect against apoptosis, potentially preserving pancreatic function 2

Weight Loss and Appetite Regulation

• Tirzepatide's weight loss effects are mediated through multiple pathways: central appetite suppression via hypothalamic neurons, delayed gastric emptying through vagal nerve signaling, and increased energy expenditure 2
• The anorexigenic (appetite-suppressing) effects are potentiated by the dual GIP-GLP-1 activation, producing more powerful satiety signals than single-receptor agonists 2
• Delayed gastric emptying is achieved by inhibiting gastric peristalsis while increasing pyloric tone, mediated through the vagus nerves 2

Cardiovascular and Metabolic Effects

• Tirzepatide produces broader cardiometabolic improvements, including blood pressure reduction through multiple mechanisms, and liver fat reduction with significant decreases in both hepatic steatosis and visceral adipose tissue 2
• The medication improves lipid profiles, including superior triglyceride reduction and better fasting glucose control compared to single-receptor GLP-1 agonists 2

Unique Pharmacological Considerations

• Tirzepatide binds to the GIP receptor but its affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1, yet it still produces superior clinical effects 2, 4
• In vitro studies reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation, suggesting tirzepatide does not have a classical co-activating mode of action in humans 4
• The mechanism leverages the natural incretin system, where GIP and GLP-1 are incretin hormones released from intestinal cells in response to nutrient intake, producing synergistic effects on insulin response and glucagon suppression 2

Clinical Implications of Mechanism

• Tirzepatide improves insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, associated with lower prandial insulin and glucagon concentrations 3
• The glucose-dependent nature of insulin stimulation and glucagon suppression explains the low likelihood of hypoglycemia with tirzepatide 2
• Much of the glucose-lowering and weight loss effects are due to effects on gastric emptying, rather than pancreatic islet effects alone 2