What is the recommended initial dose and monitoring plan for Zepbound (tirzepatide) in a patient with type 2 diabetes, considering age, weight, body mass index (BMI), renal function, and history of pancreatitis?

How to Prescribe Zepbound (Tirzepatide)

Start Zepbound at 2.5 mg subcutaneously once weekly for 4 weeks, then increase to 5 mg once weekly, with further escalation to 10 mg and ultimately 15 mg at 4-week intervals based on glycemic response and tolerability. 1, 2

Initial Dosing Protocol

• Week 1-4: Administer 2.5 mg subcutaneously once weekly 1, 2
• Week 5-8: Increase to 5 mg once weekly 1, 2
• Week 9-12: If additional glycemic control or weight loss is needed, escalate to 10 mg once weekly 1, 2
• Week 13+: For maximum glycemic effect, advance to 15 mg once weekly after at least 4 weeks on the 10 mg dose 2

The 4-week intervals between dose escalations allow adequate time for gastrointestinal adaptation and assessment of glycemic response. 1

Pre-Initiation Medication Adjustments

Reduce total daily insulin dose by approximately 20% when starting tirzepatide to prevent hypoglycemia, with close glucose monitoring for the first 4 weeks and further adjustments as needed. 1

• Sulfonylureas: Consider discontinuing or significantly reducing the dose, as hypoglycemia risk increases when combined with tirzepatide 1
• Metformin and SGLT2 inhibitors: Continue without dose adjustment—these provide complementary cardiovascular and renal benefits 1
• DPP-4 inhibitors: Discontinue before starting tirzepatide, as the mechanisms overlap 1

Absolute Contraindications

Do not prescribe Zepbound if the patient has: 1, 2

• Personal or family history of medullary thyroid cancer
• Multiple endocrine neoplasia type 2 (MEN2)
• Severe hypersensitivity to tirzepatide

Special Considerations Based on Patient Factors

History of Pancreatitis

Use extreme caution or avoid tirzepatide in patients with prior pancreatitis. While adjudication-confirmed pancreatitis rates are low (≤1%) across all doses 3, case reports demonstrate temporal associations between tirzepatide initiation and acute pancreatitis 4. Educate patients to report severe abdominal pain immediately, and discontinue permanently if pancreatitis is confirmed. 1

Renal Function

No dose adjustment is required for any level of renal function down to eGFR ≥30 mL/min/1.73 m². 1, 2 Tirzepatide slows eGFR decline by 2.2 mL/min/1.73 m² per year and reduces UACR by 31-55% in patients with baseline albuminuria. 1

Age, Weight, and BMI

Tirzepatide is particularly appropriate for patients with obesity and type 2 diabetes, with expected weight loss of 6.2-12.9 kg and HbA1c reduction of 1.87-2.59%. 1 No specific dose adjustments are required based on age, weight, or BMI—follow the standard titration schedule. 1, 2

Gastroparesis or Prior Gastric Surgery

Use with caution in patients with clinically meaningful gastroparesis or prior gastric surgery, including bariatric surgery, as tirzepatide delays gastric emptying. 2 For perioperative management, be aware this may increase aspiration risk during anesthesia. 2

Monitoring Plan

• Weeks 1-4: Monitor glucose closely, especially if on insulin or sulfonylureas 1
• Week 12: Reassess HbA1c and advance to the next dose level if not at individualized target 1
• Ongoing: Monitor for gastrointestinal symptoms (nausea 14-26%, diarrhea 11-15%, vomiting 5-13%) which are typically mild to moderate and dose-dependent 5, 3
• Throughout treatment: Watch for signs of pancreatitis (severe abdominal pain, nausea, vomiting) 1, 4

Expected Hypoglycemia Rates

Hypoglycemia risk is minimal when tirzepatide is used alone or with metformin. In the SURPASS-6 trial, tirzepatide demonstrated 0.4 events per patient-year compared to 4.4 events per patient-year with prandial insulin. 5 However, when combined with insulin or sulfonylureas, reduce doses of these agents to prevent hypoglycemia. 1

Common Pitfalls to Avoid

• Advancing doses too quickly: The 4-week intervals are essential for GI adaptation—rushing escalation increases nausea, vomiting, and drug discontinuation (10% at 15 mg dose) 3
• Failing to reduce insulin doses: Not reducing insulin by 20% at initiation leads to unnecessary hypoglycemia 1
• Combining with DPP-4 inhibitors: This combination is contraindicated due to overlapping mechanisms 1
• Ignoring pancreatitis warning signs: While rare, acute pancreatitis can occur and requires immediate discontinuation 4, 3
• Prescribing in patients with MEN2 or medullary thyroid cancer history: This is an absolute contraindication 1, 2