Tirzepatide is the Medication That is Both GLP-1 and GIP Receptor Agonist in the US
Tirzepatide (brand name MOUNJARO®) is the dual GIP/GLP-1 receptor agonist medication available in the United States. 1
Mechanism of Action
Tirzepatide functions as a dual agonist that targets both:
- Glucose-dependent insulinotropic polypeptide (GIP) receptors
- Glucagon-like peptide-1 (GLP-1) receptors
This unique dual-receptor targeting mechanism provides several advantages over single GLP-1 receptor agonists:
- Tirzepatide binds to the GIP receptor with high affinity while its affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1 2
- The molecule is engineered with an imbalanced mechanism that favors GIP receptor engagement over GLP-1 receptor engagement 3
- At the GLP-1 receptor, tirzepatide shows biased signaling that favors cAMP generation over β-arrestin recruitment, which may enhance insulin secretion 3
Clinical Effectiveness
Tirzepatide has demonstrated superior efficacy compared to selective GLP-1 receptor agonists:
- Greater reductions in HbA1c (1.24% to 2.58%) and body weight (5.4-11.7 kg) than other single agents 4
- Significantly more effective in reducing HbA1c and body weight than semaglutide (a GLP-1 receptor agonist) and titrated basal insulin 4, 5
- A substantial proportion of patients (23.0% to 62.4%) achieved normoglycemia (HbA1c <5.7%) 4
- 20.7% to 68.4% of patients lost more than 10% of their baseline body weight 4
FDA Approval and Indications
Tirzepatide is FDA-approved as:
- An adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus 1
- Available in multiple dosages: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per 0.5 mL in single-dose pen or single-dose vial 1
Dosing and Administration
- Starting dose: 2.5 mg injected subcutaneously once weekly
- After 4 weeks, increase to 5 mg once weekly
- If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose
- Maximum dosage: 15 mg subcutaneously once weekly
- Can be administered at any time of day, with or without meals 1
Clinical Considerations and Cautions
- Gastrointestinal effects: Tirzepatide delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone 2
- Safety profile: Adverse events are similar to GLP-1 receptor agonists, primarily gastrointestinal (nausea, vomiting, diarrhea, and constipation) 4
- Pulmonary aspiration risk: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures 1
- Contraindications: Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 1
Emerging Applications
Beyond type 2 diabetes, tirzepatide shows promise for:
- Obesity management with weight loss comparable to bariatric surgery 2
- Metabolic dysfunction-associated steatotic liver disease (MASLD) 2
- Cardiovascular risk reduction, though dedicated cardiovascular outcome trials are ongoing 6
Tirzepatide represents a significant advancement in incretin-based therapies with its unique dual-receptor targeting mechanism, providing superior glycemic control and weight reduction compared to single GLP-1 receptor agonists.