What is the recommended starting dose and titration schedule of Zepbound (tirzepatide) for adults with obesity (BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with a weight‑related comorbidity)?

Zepbound (Tirzepatide) Dosing for Obesity Management

Start tirzepatide at 2.5 mg subcutaneously once weekly, then escalate by 2.5 mg every 4 weeks to reach a maintenance dose of 5 mg, 10 mg, or 15 mg based on efficacy and tolerability. 1

Standard Titration Schedule

The FDA-approved dosing protocol follows a structured escalation to minimize gastrointestinal adverse effects while achieving therapeutic benefit 1:

• Weeks 1-4: 2.5 mg once weekly (tolerability dose, not therapeutic) 1
• Weeks 5-8: 5 mg once weekly 1
• Weeks 9-12: 7.5 mg once weekly (if needed) 1
• Weeks 13-16: 10 mg once weekly (if needed) 1
• Weeks 17+: 15 mg once weekly (maximum dose) 1

The initial 2.5 mg dose is specifically designed to minimize gastrointestinal side effects during the first 4 weeks and is not intended for weight loss efficacy 1. Each dose escalation occurs at 4-week intervals to allow physiologic adaptation and reduce nausea, vomiting, and diarrhea 1.

Patient Eligibility Criteria

You qualify for tirzepatide if you meet one of these criteria 2:

• BMI ≥30 kg/m² (obesity) without additional requirements 2
• BMI ≥27 kg/m² with at least one weight-related comorbidity: type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease 2

Tirzepatide must be combined with a reduced-calorie diet (500-kcal deficit below daily requirements) and minimum 150 minutes per week of physical activity 2.

Expected Weight Loss Outcomes

Tirzepatide demonstrates dose-dependent efficacy 3, 4:

• 5 mg weekly: 15.0% mean weight loss at 72 weeks 3
• 10 mg weekly: 19.5% mean weight loss at 72 weeks (12.8% in patients with type 2 diabetes) 3, 4
• 15 mg weekly: 20.9% mean weight loss at 72 weeks (14.7% in patients with type 2 diabetes) 3, 4

Approximately 50-57% of patients on the 10-15 mg doses achieve ≥20% weight loss, and nearly 40% achieve ≥25% weight loss 3, 5. Weight loss is consistently greater in non-diabetic patients (15-20.9%) compared to those with diabetes (4-6.2%) 5.

Monitoring During Titration

Assess patients at specific intervals to optimize outcomes 1:

• Monthly during first 3 months: Evaluate gastrointestinal tolerance, weight loss progress, blood pressure, and signs of pancreatitis or gallbladder disease 1
• Quarterly after reaching maintenance dose: Monitor weight stability, cardiovascular risk factors, and medication adherence 1
• At 12-16 weeks on maximum tolerated dose: Evaluate treatment efficacy; discontinue if <4-5% body weight loss 1, 5

Early responders (≥5% weight loss after 3 months) should continue long-term therapy, as further weight loss is likely with continued use 2.

Common Adverse Effects and Management

Gastrointestinal effects are the most frequent adverse events, occurring primarily during dose escalation 1, 3:

• Nausea: 17-31% (dose-dependent) 1
• Diarrhea: 12-23% 1
• Vomiting: 12% 1
• Constipation: 12-18% 1

These effects are typically mild-to-moderate in severity and decrease over time 3, 4. The gradual 4-week titration schedule specifically minimizes these symptoms 1. Treatment discontinuation due to adverse events occurs in 4.3-7.1% of patients 3.

Absolute Contraindications

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

• Personal or family history of medullary thyroid cancer 2
• Multiple endocrine neoplasia syndrome type 2 (MEN2) 2
• History of severe hypersensitivity reaction to tirzepatide 1

Serious Safety Concerns Requiring Monitoring

Monitor for these rare but serious complications 1:

• Pancreatitis: Discontinue immediately if persistent severe abdominal pain occurs 1
• Gallbladder disease: Watch for cholelithiasis and cholecystitis symptoms 1
• Acute kidney injury: Use caution when initiating or escalating doses in patients with renal impairment 1
• Severe constipation/bowel obstruction: Monitor for progression to ileus 1

Special Considerations

Oral contraceptives: Advise patients to use non-oral contraception or add a barrier method for 4 weeks after initiation and each dose escalation, as tirzepatide delays gastric emptying and may affect oral medication absorption 1.

Medications with narrow therapeutic indices (e.g., warfarin): Monitor closely during titration due to potential delayed absorption from gastric emptying effects 1.

Renal impairment: No dose adjustment is necessary for mild-to-moderate renal impairment, but use caution during dose escalation 1.

Perioperative management: Consider stopping tirzepatide before elective procedures due to delayed gastric emptying and aspiration risk; the elimination half-life is 5 days 1.

Long-Term Treatment Considerations

Tirzepatide requires lifelong continuous use to maintain weight loss benefits. Discontinuation leads to substantial weight regain—withdrawing tirzepatide after initial weight loss results in a mean 14.0% weight regain over 52 weeks, whereas continued treatment maintains and augments weight reduction with an additional 5.5% loss 6. Only 16.6% of patients who discontinue maintain at least 80% of their initial weight loss, compared to 89.5% who continue treatment 6.

When to Discontinue Treatment

Stop tirzepatide if 1, 5:

• Weight loss is <4-5% after 16 weeks on the maximum tolerated dose 1
• Significant safety or tolerability issues emerge (e.g., suspected pancreatitis, severe gastrointestinal symptoms) 1
• Patient develops absolute contraindications 1

Comparative Context

Tirzepatide demonstrates superior weight loss compared to other anti-obesity medications 2:

• Tirzepatide 15 mg: 20.9% weight loss 3
• Semaglutide 2.4 mg: 14.9% weight loss 2
• Liraglutide 3.0 mg: 5.2-6.1% weight loss 2

The weight loss efficacy of tirzepatide is comparable to what has previously only been reported with bariatric surgery 5.