Initial Dose of Zepbound (Tirzepatide)
The first dose of Zepbound (tirzepatide) is 2.5 mg subcutaneously once weekly for 4 weeks, which serves as an initiation dose to improve gastrointestinal tolerability before escalating to the first therapeutic dose of 5 mg once weekly. 1
Starting Dose and Titration Protocol
- Begin with 2.5 mg subcutaneously once weekly for the first 4 weeks 1, 2, 3
- After the initial 4-week period on 2.5 mg, increase to 5 mg once weekly, which is the first maintenance dose 1
- The 2.5 mg starting dose is not intended for glycemic control but rather to minimize gastrointestinal side effects (nausea, vomiting, diarrhea) that are common with GLP-1 receptor agonist therapy 1, 4
Subsequent Dose Escalation
If additional glycemic control is needed after at least 4 weeks on each dose:
- Escalate from 5 mg to 10 mg once weekly after a minimum of 4 weeks 1, 3
- Further escalate from 10 mg to 15 mg once weekly after a minimum of 4 weeks if maximum glycemic control is required 1, 2
- Each dose escalation occurs in 2.5 mg increments at 4-week intervals 2, 3
Administration Considerations
- Administer as a subcutaneous injection once weekly at any time of day, without regard to meals 1
- No dosage adjustments are required for renal impairment, including patients with mild to moderate kidney dysfunction 1
Concomitant Medication Adjustments
- Reduce insulin or insulin secretagogue doses when initiating tirzepatide to minimize hypoglycemia risk, as recommended by the American College of Cardiology 1
- Hypoglycemia rates with tirzepatide monotherapy or with metformin are low (1-2% experiencing glucose <54 mg/dL), but increase when combined with insulin 2, 3
Common Pitfalls to Avoid
- Do not skip the 2.5 mg initiation phase—this gradual titration significantly reduces gastrointestinal adverse events that lead to treatment discontinuation 1, 4
- Gastrointestinal side effects (nausea 13-24%, diarrhea 15-21%, vomiting 6-10%) are most common during dose escalation and typically decrease over time 2, 3
- Be aware that tirzepatide delays gastric emptying, which may increase aspiration risk during anesthesia in the perioperative setting 1