What type of drug is Mounjaro (tirzepatide), a dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist, for an adult patient with type 2 diabetes?

Mounjaro: Dual GIP/GLP-1 Receptor Agonist

Mounjaro (tirzepatide) is a first-in-class dual incretin agonist that activates both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, approved for type 2 diabetes management and obesity treatment. 1, 2

Drug Classification and Mechanism

Tirzepatide represents a distinct drug class—"Dual GIP and GLP-1 RA"—separate from traditional GLP-1 receptor agonists. 1 This unimolecular dual agonist binds to both GIP and GLP-1 receptors, though its affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1. 1

Key Mechanisms of Action

• Dual receptor activation provides enhanced metabolic benefits including delayed gastric emptying, suppressed appetite, improved insulin secretion, decreased glucagon secretion, and increased pancreatic β-cell growth. 1, 3

• 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. 1

• The glucose-dependent nature of both insulin stimulation and glucagon suppression explains the minimal hypoglycemia risk when used as monotherapy. 1, 4

Clinical Indications

Type 2 Diabetes Management

• FDA-approved as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 2

• Tirzepatide should be prioritized for patients requiring maximal HbA1c reduction (>2% needed) who have failed other agents, achieving HbA1c reductions ranging from 1.87% to 2.59%. 4, 5

• 23.0% to 62.4% of patients achieve HbA1c <5.7% (normal range), representing unprecedented normoglycemia rates for a single agent. 1, 6

Obesity Treatment

• FDA-approved in November 2023 for obesity management in adults with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity. 1

• Demonstrates superior weight loss (20.9%) compared to semaglutide (14.9%), representing the most effective pharmacological option currently available. 1, 6

• 20.7% to 68.4% of patients lose more than 10% of baseline body weight, approaching bariatric surgery results. 4, 6

Administration and Dosing

• Administered as once-weekly subcutaneous injection available in single-dose prefilled pens and vials. 1, 2

• Dosing schedule: Start at 5 mg weekly, titrate upward every 4 weeks based on tolerance to maximum dose of 15 mg weekly. 1, 4

• The dose-dependent efficacy applies to both glycemic control and weight loss, with higher doses producing greater benefits. 4, 7

Critical Safety Considerations

Contraindications

• Absolute contraindication: Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2. 1

• Cannot be combined with other GLP-1 receptor agonists or DPP-4 inhibitors due to overlapping mechanisms and lack of additional benefit. 1, 4

Common Adverse Effects

• Gastrointestinal effects predominate: Nausea, vomiting, diarrhea, and constipation are most common, typically mild-to-moderate and transient. 1, 2, 6

• Delayed gastric emptying is a persistent class effect, creating aspiration risk during anesthesia even after extended fasting periods. 1, 4

• Serious but rare risks include pancreatitis and gallbladder disease, though causality has not been definitively established. 1, 4

Important Clinical Distinctions

Cardiovascular Outcomes

• Tirzepatide does NOT reduce all-cause mortality or major adverse cardiovascular events (MACE) compared to usual care, unlike traditional GLP-1 receptor agonists such as semaglutide which demonstrate proven mortality and cardiovascular benefits. 4, 5

• For patients with established cardiovascular disease, semaglutide should be prioritized over tirzepatide due to proven 20-26% reduction in cardiovascular death, nonfatal MI, or stroke. 1, 5

• Tirzepatide meets cardiovascular safety criteria with MACE-4 hazard ratios <1.0 and upper confidence bounds <1.3, but lacks proven benefit. 1, 6

Hypoglycemia Risk

• Minimal hypoglycemia risk as monotherapy or with metformin due to glucose-dependent mechanism. 4, 5

• Risk increases significantly when combined with insulin or sulfonylureas, requiring dose reduction of these agents by 10-20%. 1, 4

Clinical Positioning Algorithm

For type 2 diabetes with obesity but no cardiovascular disease: Prioritize tirzepatide for maximal HbA1c reduction and weight loss. 5

For type 2 diabetes with established cardiovascular disease: Prioritize GLP-1 receptor agonists (semaglutide) over tirzepatide for proven mortality and MACE reduction. 5

For obesity without diabetes: Tirzepatide 15 mg weekly achieves greatest weight loss among available pharmacological options. 1, 4

For metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity: Consider tirzepatide due to substantial hepatic steatosis reduction and weight loss effects. 4

Cost Considerations

• Median average wholesale price: $1,283 per 30-day supply for tirzepatide 15 mg pen. 1

• Lifelong treatment is typically necessary to maintain weight loss and glycemic benefits, as discontinuation results in regain of one-half to two-thirds of lost weight within 1 year. 1