What is Mounjaro (Tirzepatide)?
Mounjaro (tirzepatide) is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus, representing a novel therapeutic approach that produces superior glycemic control and weight loss compared to traditional GLP-1 receptor agonists alone. 1, 2
Mechanism of Action
Tirzepatide is uniquely engineered to activate both GIP and GLP-1 receptors, which are key mediators of glucose-dependent insulin secretion from pancreatic beta cells. 1, 3 The drug binds to the GIP receptor with high affinity, but its affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1. 1
Dual Receptor Activation Effects:
Insulin secretion: Both GIP and GLP-1 receptor activation stimulate insulin release from pancreatic beta cells in response to elevated postprandial glucose levels, with minimal effect when glucose is normal—explaining the low risk of hypoglycemia. 1
Glucagon regulation: GLP-1 receptor activation inhibits glucagon secretion, while GIP receptor activation augments glucagon secretion during euglycemia or hypoglycemia but inhibits it during hyperglycemia. 1
Gastric emptying: Much of the glucose-lowering effect occurs through delayed gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone, mediated through vagal nerve pathways. 1
Appetite suppression: GIP and GLP-1 receptors in the hypothalamus and brainstem nuclei regulate appetite, satiety, and energy expenditure. 1
Clinical Efficacy
Tirzepatide demonstrates unprecedented effectiveness for a single agent in type 2 diabetes management. 3
Glycemic Control:
- HbA1c reductions of 1.24% to 2.58% across the SURPASS 1-5 clinical trial program. 3
- 23.0% to 62.4% of patients achieved HbA1c < 5.7% (normoglycemic range). 3
- Superior to semaglutide 1 mg weekly and titrated basal insulin in head-to-head comparisons. 1, 3
Weight Loss:
- Body weight reductions of 5.4 to 11.7 kg (mean weight loss 6.2 to 12.9 kg depending on dose). 3, 4
- 20.7% to 68.4% of patients lost more than 10% of baseline body weight. 3
- Greater weight loss than semaglutide despite similar appetite reduction effects. 3
Cardiovascular Benefits:
- Reduces rates of non-fatal myocardial infarction, stroke, and cardiovascular death in patients with type 2 diabetes and obesity. 1
- Meta-analysis showed hazard ratios < 1.0 for all cardiovascular events analyzed, with upper confidence interval bounds < 1.3, fulfilling cardiovascular safety criteria. 3
Pharmacokinetics
Tirzepatide is molecularly modified to prevent rapid degradation by dipeptidyl peptidase-4, resulting in a prolonged elimination half-life that allows for once-weekly subcutaneous administration. 1 This long-acting formulation provides more stable plasma drug concentrations and improved gastrointestinal tolerability compared to short-acting agents. 1
Approved Indications
FDA-approved as adjunct therapy to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 2, 5 The drug is also under investigation for chronic weight management, major adverse cardiovascular events, heart failure with preserved ejection fraction, and non-alcoholic steatohepatitis. 4
Dosing
Available in 5 mg, 10 mg, and 15 mg once-weekly subcutaneous injections, with dose titration recommended to optimize efficacy while minimizing gastrointestinal side effects. 3, 4
Adverse Effects
The safety profile is similar to GLP-1 receptor agonists, with dose-dependent gastrointestinal effects being most common:
- Nausea, vomiting, diarrhea, and constipation (more common at higher doses). 3
- Low risk of hypoglycemia when used without insulin or insulin secretagogues. 1, 4
- Should be avoided in patients with gastroparesis. 1
- Slow dose titration improves gastrointestinal tolerability. 1
Important Peri-operative Considerations
A critical caveat for clinicians: Tirzepatide significantly delays gastric emptying through vagally-mediated mechanisms, leading to increased fasting and postprandial gastric volumes. 1 This raises concerns about pulmonary aspiration risk during anesthesia. Current evidence suggests withholding the drug for at least three half-lives before elective surgery for patients using it for weight management, though definitive guidance is lacking. 1