Converting from Ozempic (Semaglutide) to Zepbound (Tirzepatide)

Discontinuation and Initiation Strategy

The American College of Cardiology recommends stopping semaglutide and beginning tirzepatide at 2.5 mg subcutaneously once weekly, as the 2.5 mg starting dose is specifically designed to minimize gastrointestinal side effects 1
The initial dose of tirzepatide should be 2.5 mg, which serves as a tolerability primer, and then escalate by 2.5 mg every 4 weeks until reaching the target maintenance dose based on efficacy and tolerability 1

The standard titration protocol for tirzepatide involves escalating the dose by 2.5 mg every 4 weeks, with a target maintenance dose of 5 mg, 10 mg, or 15 mg based on efficacy and tolerability 1
The titration schedule is as follows: Week 0-4: 2.5 mg once weekly, Week 4-8: 5 mg once weekly, Week 8-12: 7.5 mg once weekly, Week 12-16: 10 mg once weekly, Week 16+: 12.5 mg once weekly, and Week 20+: 15 mg once weekly (if needed) 1
The 15 mg dose provides maximum efficacy with 20.9% weight loss at 72 weeks compared to 15.0% with 5 mg 1

The American College of Cardiology recommends assessing effectiveness and safety at least monthly for the first 3 months during dose escalation 1
Reduce insulin or sulfonylurea doses by 20-30% at conversion to minimize hypoglycemia risk, as tirzepatide demonstrates superior glucose-lowering compared to semaglutide 2
Evaluate treatment efficacy at 12-16 weeks on the maximum tolerated dose; consider discontinuation if less than 4-5% body weight loss at 16 weeks 1

The gradual titration schedule specifically mitigates gastrointestinal side effects—do not accelerate dose escalation even if the patient tolerated high-dose semaglutide well 3, 1
Counsel patients to eat smaller portions and that nausea is typically self-limited with longer-acting agents 3
If more than 2 consecutive doses are missed, resume at the same dose if previously well-tolerated; otherwise lower the next dose, and if 3+ consecutive doses are missed, restart the titration schedule 4, 1

For patients on oral contraceptives, advise non-oral contraception or addition of a non-oral method for 4 weeks after each dose escalation, as tirzepatide may delay gastric emptying and affect oral medication absorption 1
For patients with diabetic retinopathy, exercise particular caution, as semaglutide has been associated with diabetic retinopathy complications related to rapid glucose reductions, and ensure recent ophthalmologic examination before conversion 3
Contraindications remain the same: Personal or family history of medullary thyroid cancer, MEN2 syndrome, and history of serious hypersensitivity reactions 5

Tirzepatide 15 mg produces 20.2% weight reduction vs 13.7% with semaglutide at 72 weeks in patients with T2D and obesity 6

Do not combine tirzepatide with other GLP-1 receptor agonists or DPP-4 inhibitors, as they work through overlapping GLP-1 signaling pathways and are not approved for concurrent use 2, 4
Monitor medications with narrow therapeutic indices (e.g., warfarin) closely during titration due to potential delayed absorption from gastric emptying effects 1