Initial Dosing for Zepbound (Tirzepatide)
Start Zepbound at 2.5 mg subcutaneously once weekly for the first 4 weeks, then increase to 5 mg weekly. 1, 2
Standard Titration Schedule
The FDA-approved titration protocol follows a structured 4-week escalation pattern 1, 2:
- Weeks 1-4: 2.5 mg once weekly (tolerability assessment dose, not therapeutic)
- Weeks 5-8: 5 mg once weekly (first therapeutic dose)
- Weeks 9-12: 10 mg once weekly (if additional weight loss needed)
- Week 13+: 15 mg once weekly (maximum dose, if tolerated and needed)
Each dose increase occurs after 4 weeks at the current dose 1, 2. The 2.5 mg starting dose specifically minimizes gastrointestinal side effects during initial treatment 2.
Key Prescribing Details
Injection technique: Administer subcutaneously once weekly on the same day each week, at any time of day, with or without meals 3. The injection site can be abdomen, thigh, or upper arm 1.
Maintenance dosing: The therapeutic maintenance dose is 5 mg, 10 mg, or 15 mg weekly based on efficacy and tolerability 2. Most patients will require escalation beyond the 2.5 mg starting dose to achieve meaningful weight loss 1.
Critical Pre-Treatment Screening
Absolute contraindications that must be ruled out before initiating 1, 2:
- Personal or family history of medullary thyroid cancer
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
- History of severe hypersensitivity to tirzepatide
Required baseline assessments 1:
- BMI ≥30 kg/m² (obesity) OR BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease)
- Lipid panel (total cholesterol, LDL, HDL, triglycerides)
- Comprehensive metabolic panel including renal function
- Screen for gastroparesis or severe gastrointestinal motility disorders
Concomitant Medication Adjustments
If patient is taking insulin: Reduce basal insulin by 20% immediately when starting tirzepatide to prevent hypoglycemia 1. For patients with HbA1c <8%, consider a more aggressive 30% reduction 1.
If patient is taking sulfonylureas: Discontinue or reduce dose by 50% to prevent hypoglycemia 1.
Oral contraceptives: Women using oral contraceptives should switch to a non-oral method or add barrier contraception for 4 weeks after initiation and after each dose escalation due to delayed gastric emptying 2.
Monitoring During Titration
Every 4 weeks during dose escalation 1, 2:
- Weight and blood pressure
- Gastrointestinal tolerance (nausea, vomiting, diarrhea)
- Signs of pancreatitis (persistent severe abdominal pain)
- Signs of gallbladder disease
Efficacy assessment at 12-16 weeks on maximum tolerated dose: Expect at least 4-5% body weight loss to justify continuation 3, 2. If weight loss is <5% after 3 months at therapeutic dose, consider discontinuation and alternative approaches 1.
Common Pitfalls to Avoid
Do not assess efficacy at 2.5 mg: This starting dose is solely for tolerability, not weight loss efficacy 3. Premature evaluation leads to inappropriate discontinuation.
Do not skip the titration schedule: Rapid escalation significantly increases gastrointestinal adverse events (nausea occurs in 17-31% of patients) 2. Slow titration improves tolerability 1.
Do not forget lifestyle modifications: Tirzepatide must be combined with a reduced-calorie diet (500-kcal deficit) and minimum 150 minutes per week of physical activity 1. Medication alone without lifestyle modification yields suboptimal results 1.
Do not overlook medication interactions: Tirzepatide delays gastric emptying, which can affect absorption of oral medications with narrow therapeutic indices (e.g., warfarin) 2. Monitor these medications closely 1.
Expected Outcomes
With proper titration to therapeutic doses, tirzepatide achieves mean weight loss of 15-20.9% at 72 weeks, with the 15 mg dose producing the greatest effect 1, 2, 4. Approximately 91% of patients achieve ≥5% weight loss, and 50-57% achieve ≥20% weight loss with the 10-15 mg doses 4.