How does Zepbound (tirzepatide) work?

How Zepbound (Tirzepatide) Works

Zepbound (tirzepatide) is a dual-hormone agonist that activates both GLP-1 and GIP receptors, producing unprecedented weight loss and glycemic control through multiple complementary mechanisms including appetite suppression, delayed gastric emptying, enhanced insulin secretion, and increased energy expenditure. 1

Dual Receptor Mechanism of Action

Tirzepatide is engineered as a synthetic peptide that simultaneously targets two key incretin hormone receptors 2, 3:

• GLP-1 receptor activation suppresses appetite through central nervous system effects on the hypothalamus, delays gastric emptying, stimulates glucose-dependent insulin release, decreases glucagon secretion, and promotes pancreatic β-cell growth 1, 3
• GIP receptor activation enhances the metabolic effects beyond what GLP-1 alone can achieve, though the exact mechanism in humans remains under investigation 2, 4
• The molecule is acylated to bind albumin, allowing once-weekly subcutaneous dosing 5

Superior Metabolic Effects

Tirzepatide demonstrates superior weight loss (20.9%) compared to semaglutide (14.9%), representing the most effective single-agent pharmacotherapy for obesity currently available. 1

The dual agonism produces several metabolic benefits 2, 3, 5:

• Insulin sensitivity improvement greater than selective GLP-1 agonists, with enhanced insulin secretory responses and lower prandial insulin requirements 2
• Body weight reduction of 5.4-11.7 kg in clinical trials, with 20.7-68.4% of patients achieving >10% weight loss 2
• Glycemic control with HbA1c reductions of 1.24-2.58%, with 23.0-62.4% of patients reaching normoglycemia (HbA1c <5.7%) 2
• Lipid metabolism improvement including triglyceride reduction and LDL cholesterol lowering 3

Incretin Hormone Physiology

The mechanism leverages the natural incretin system 6, 7:

• GIP and GLP-1 are incretin hormones released from intestinal cells in response to nutrient intake 3, 7
• These hormones are responsible for up to 65% of postprandial insulin secretion 5
• Co-activation of both receptors produces synergistic effects on insulin response and glucagon suppression that exceed either hormone alone 7
• The glucose-dependent nature of insulin stimulation explains the minimal hypoglycemia risk when used as monotherapy 1

Appetite and Satiety Regulation

Tirzepatide's weight loss effects are mediated through multiple pathways 6, 1:

• Central appetite suppression through hypothalamic GLP-1 receptor activation 1
• Delayed gastric emptying reducing food intake through increased satiety 6, 3
• Increased energy expenditure and enhanced lipolysis and lipid oxidation 6
• These anorexigenic effects are potentiated by the dual GIP-GLP-1 activation 6

Cardiovascular and Metabolic Benefits

Beyond glucose and weight control, tirzepatide produces broader cardiometabolic improvements 1, 3:

• Blood pressure reduction through multiple mechanisms 3
• Cardiovascular risk reduction with meta-analysis showing hazard ratios <1.0 for MACE-4 events across clinical trials 2
• Liver fat reduction with significant decreases in both hepatic steatosis and visceral adipose tissue, showing promise for metabolic dysfunction-associated steatotic liver disease 6

Molecular Pharmacology Considerations

The exact contribution of GIP receptor activation remains an area of active investigation 4:

• Tirzepatide has approximately five times less affinity for the GLP-1 receptor compared to endogenous GLP-1 1
• In vitro studies suggest a biased GLP-1 receptor activation profile and potential GIP receptor downregulation 4
• The clinical superiority over selective GLP-1 agonists suggests GIP receptor activation provides meaningful therapeutic benefit, though the precise mechanism in humans differs from rodent models 2, 4

Clinical Implications

Tirzepatide must be used in conjunction with lifestyle modifications including reduced-calorie diet and increased physical activity, and may require lifelong use as significant weight regain occurs after cessation. 1

The medication is administered as a once-weekly subcutaneous injection, starting at 5 mg weekly with gradual titration to minimize gastrointestinal side effects 1. Common adverse effects include nausea, vomiting, diarrhea, and constipation, similar to selective GLP-1 agonists but typically mild-to-moderate and decreasing over time 1, 2. The drug is contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1.