Zepbound - Drug Monograph

Introduction

Zepbound (tirzepatide) is a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved by the FDA in November 2023 for chronic weight management. This dual agonist represents a significant advancement in pharmacotherapy for obesity, building upon the success of GLP-1 receptor agonists while incorporating additional mechanisms through GIP receptor activation.

Mechanism of Action

Tirzepatide is a single peptide molecule that activates both GLP-1 and GIP receptors, creating a synergistic effect on weight regulation and glucose control. The drug works through multiple mechanisms:

• GLP-1 receptor agonism: Enhances glucose-dependent insulin secretion, suppresses glucagon secretion, delays gastric emptying, and promotes satiety through central nervous system effects
• GIP receptor agonism: Complements GLP-1 effects by further enhancing insulin sensitivity, promoting lipid metabolism, and potentially amplifying central nervous system satiety signals
• The combined receptor activation results in reduced appetite, increased feelings of fullness, and improved metabolic parameters beyond what either pathway achieves alone

Indications

Zepbound is indicated for:

• Chronic weight management in adults with obesity (BMI ≥30 kg/m²)
• Overweight adults (BMI ≥27 kg/m²) with at least one weight-related comorbid condition (such as hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease)
• Use as an adjunct to reduced-calorie diet and increased physical activity

Dosage and Administration

• Administer subcutaneously in abdomen, thigh, or upper arm
• Rotate injection sites with each administration
• May be administered with or without meals
• If a dose is missed, administer within 4 days; if more than 4 days have passed, skip missed dose and resume regular schedule

• Renal impairment: No dose adjustment needed for mild to moderate impairment; use caution in severe impairment
• Hepatic impairment: No dose adjustment needed
• Geriatric patients: No dose adjustment needed
• Pediatrics: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• History of serious hypersensitivity reaction to tirzepatide or any component
• Personal or family history of medullary thyroid carcinoma
• Patients with Multiple Endocrine Neoplasia syndrome type 2
• Pregnancy

Warnings and Precautions

• Thyroid tumors have occurred in rodent studies; relevance to humans unknown
• Patients should be counseled regarding potential risk

• Acute pancreatitis: Discontinue if suspected
• Hypoglycemia: Increased risk when used with insulin secretagogues or insulin
• Acute kidney injury: Monitor renal function in patients reporting severe gastrointestinal reactions
• Severe gastrointestinal disease: May exacerbate existing conditions
• Diabetic retinopathy: Monitor patients with history of retinopathy
• Acute gallbladder disease: Has been reported with GLP-1 receptor agonists

Drug Interactions

• Insulin and insulin secretagogues: Increased risk of hypoglycemia (dose reduction may be needed)
• Oral medications: Delayed gastric emptying may affect absorption of orally administered drugs
• Warfarin: Monitor INR more frequently during initiation and dose changes

Adverse Effects

• Nausea (24%)
• Diarrhea (20%)
• Vomiting (12%)
• Constipation (12%)
• Dyspepsia (11%)

• Injection site reactions
• Fatigue
• Decreased appetite
• Abdominal pain
• Headache
• Dizziness

• Acute pancreatitis
• Severe hypoglycemia (when combined with other agents)
• Acute kidney injury
• Allergic reactions
• Gallbladder disease

Monitoring Parameters

• BMI and weight
• Renal function
• Liver function
• HbA1c (if diabetic)
• Thyroid function (baseline calcitonin not required)
• Cardiovascular risk factors

• Weight and BMI at regular intervals
• Gastrointestinal tolerance
• Signs of pancreatitis (abdominal pain, nausea, vomiting)
• Renal function in patients with gastrointestinal symptoms
• Blood glucose (especially when used with other antidiabetic agents)
• Nutritional status

Patient Education

• Administer once weekly on the same day each week
• Proper injection technique and site rotation
• Gradual dose escalation to minimize gastrointestinal effects
• Report severe or persistent abdominal pain immediately
• Maintain adequate hydration, especially with gastrointestinal symptoms
• Importance of concomitant lifestyle modifications
• Recognition of hypoglycemia symptoms if using with other antidiabetic agents
• Pregnancy prevention required during treatment
• Report any neck masses, dysphagia, dyspnea, or persistent hoarseness

• Refrigerate at 2°C to 8°C (36°F to 46°F)
• May be stored at room temperature (up to 30°C/86°F) for up to 21 days
• Protect from light
• Do not freeze

References

1. FDA Approval Package: Zepbound (tirzepatide). November 2023. 2. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387:205-216. 3. Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385:503-515. 4. Zepbound [package insert]. Indianapolis, IN: Eli Lilly and Company; 2023. 5. Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021;12:143-157. 6. American Diabetes Association. Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1-S276.