What is the typical dosing regimen for tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist) for weight loss?

Tirzepatide Dosing for Weight Loss

Dosing Regimen

Start tirzepatide at 2.5 mg subcutaneously once weekly and titrate upward every 4 weeks through 5 mg, 7.5 mg, 10 mg, 12.5 mg, to a maximum maintenance dose of 15 mg weekly for optimal weight loss. 1

The specific titration schedule is:

• Week 1-4: 2.5 mg once weekly (tolerability assessment, not therapeutic dose) 1, 2
• Week 5-8: 5 mg once weekly 1
• Week 9-12: 7.5 mg once weekly 1
• Week 13-16: 10 mg once weekly 1
• Week 17-20: 12.5 mg once weekly 1
• Week 21+: 15 mg once weekly (maximum maintenance dose) 1

The 2.5 mg starting dose is specifically for tolerability assessment and should not be used to evaluate weight loss efficacy—therapeutic doses begin at 5 mg. 2

Dose-Dependent Efficacy

Tirzepatide demonstrates clear dose-dependent weight loss at 72 weeks:

• 5 mg weekly: 15.0% mean weight loss 1, 3
• 10 mg weekly: 19.5% mean weight loss 1, 3
• 15 mg weekly: 20.9% mean weight loss (maximum efficacy) 1, 3
• Placebo: 3.1% weight loss 1, 3

Between 85-91% of patients achieve ≥5% total body weight loss, 50-57% achieve ≥20% weight loss on the 10-15 mg doses, and nearly 40% on the 15 mg dose achieve ≥25% weight loss. 1, 3 This weight loss magnitude is comparable to what has previously only been achieved with bariatric surgery. 1, 2

Patient Selection Criteria

Eligible patients include:

• BMI ≥30 kg/m² (obesity), OR 1, 4
• BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease) 1, 4

Absolute contraindications:

• Personal or family history of medullary thyroid carcinoma 1, 4
• Multiple Endocrine Neoplasia syndrome type 2 1, 4
• Severe gastrointestinal disease including gastroparesis 4

Use with caution in:

• eGFR 15-30 mL/min/1.73 m² (potential risk of acute kidney injury during dose escalation) 4
• eGFR <15 mL/min/1.73 m² or dialysis (avoid—limited clinical experience) 4

Monitoring Schedule

Initial phase (first 3 months):

• Assess effectiveness and safety at least monthly 1, 4

Maintenance phase (after 3 months):

• Monitor at least quarterly 1, 4

Specific parameters to monitor:

• Weight and BMI 1
• Blood pressure 1
• Gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation) 1, 4
• Signs of cholelithiasis and gallstone-related complications 1, 4
• Cardiac arrhythmias/tachycardia (consider beta blockers if symptomatic) 4, 2
• Delayed absorption of oral medications with narrow therapeutic indices 1, 4

Treatment Evaluation and Discontinuation Criteria

Evaluate treatment response at 12-16 weeks on the maximum tolerated therapeutic dose (5 mg, 10 mg, or 15 mg). 2 Do not assess efficacy at one month on the 2.5 mg starting dose, as this is only for tolerability. 2

Consider discontinuing tirzepatide if:

• Less than 4-5% body weight loss at 16 weeks on the maximum tolerated dose 2

This criterion is extrapolated from other GLP-1 receptor agonist guidelines (specifically liraglutide), as tirzepatide-specific discontinuation criteria are not yet established in guidelines. 2

Managing Gastrointestinal Side Effects

The most common adverse events are gastrointestinal:

• Nausea (31%) 2, 5
• Diarrhea (23%) 2, 5
• Vomiting (12%) 2, 5
• Constipation (5%) 2, 5

Management strategies:

• Use the slow upward titration schedule as outlined above 4, 2
• Reduce meal size 4, 2
• Limit alcohol and carbonated drinks 4, 2
• Avoid high-fat diets 4, 2

Most gastrointestinal side effects are mild to moderate in severity and occur primarily during dose escalation. 3, 6 Treatment discontinuation due to adverse events occurs in 4.3-7.1% of patients on therapeutic doses. 3

Critical Clinical Pearls

Long-term use is necessary to maintain weight loss benefits. Weight regain occurs rapidly when treatment is discontinued—this is a class effect of anti-obesity medications. 4, 2 Tirzepatide must be used in conjunction with lifestyle modifications for optimal results. 4, 2

Tirzepatide produces greater weight loss in non-diabetic individuals (15-20.9%) compared to those with type 2 diabetes (4-6.2%). 1, 2 In head-to-head comparison, tirzepatide achieved 20.2% mean weight reduction versus 13.7% with semaglutide at 72 weeks. 1, 2

Cost Considerations

The average wholesale price is $1,272 per 30-day supply, with national average drug acquisition cost of $1,017. 1, 4 Insurance coverage varies significantly and may limit access. 1, 4