What is the 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

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

Dosing Algorithm

The titration schedule follows a structured escalation pattern to minimize gastrointestinal side effects while maximizing efficacy:

• Week 1-4: 2.5 mg once weekly (starting dose)
• Week 5-8: 5 mg once weekly
• Week 9-12: 7.5 mg once weekly
• Week 13-16: 10 mg once weekly
• Week 17-20: 12.5 mg once weekly
• Week 21 onward: 15 mg once weekly (maximum dose) 1

The slow upward titration is critical for tolerability, as gastrointestinal adverse events (nausea 31%, diarrhea 23%, vomiting 12%, constipation 5%) are dose-dependent and most problematic during dose escalation. 2

Expected Weight Loss by Dose

Tirzepatide demonstrates clear dose-dependent efficacy at 72 weeks:

• 5 mg weekly: 15.0% mean weight loss 1
• 10 mg weekly: 19.5% mean weight loss 1
• 15 mg weekly: 20.9% mean weight loss (maximum efficacy) 1, 2
• Placebo with lifestyle modifications: 3.1% weight loss 1

Between 20.7-68.4% of patients achieve ≥10% total body weight loss, and nearly 40% on the 15 mg dose achieve ≥25% weight loss. 2 Maximum reported weight loss in clinical trials reached 23.6 kg (52 lb) or 22.5% body weight. 3

Patient Selection Criteria

Eligible patients include:

• BMI ≥30 kg/m² (obesity), OR
• BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease) 1, 2

Absolute contraindications:

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

Use with caution in:

• Kidney disease (risk of acute kidney injury from dehydration due to GI side effects) 1
• History of pancreatitis 4

Monitoring Schedule

• First 3 months: Assess effectiveness and safety at least monthly 1
• After 3 months: Continue monitoring at least quarterly 1
• Treatment evaluation timepoint: Assess at 12-16 weeks on maximum tolerated dose; consider discontinuation if <4-5% body weight loss at 16 weeks 2

Specific monitoring parameters:

• Weight and BMI at each visit
• Blood pressure (tirzepatide may elevate heart rate—monitor for cardiac arrhythmias/tachycardia) 2
• Gastrointestinal symptoms
• Delayed absorption of oral medications with narrow therapeutic indices 1, 2
• Signs of cholelithiasis and gallstone-related complications 2

Managing Gastrointestinal Side Effects

The most common adverse events are gastrointestinal and typically mild-to-moderate and transient. 5 Management strategies include:

• Slow upward titration schedule (as outlined above) 1
• Reduce meal size 1
• Limit alcohol and carbonated drinks 1
• Avoid high-fat diets 1
• Consider temporary dose reduction if symptoms are severe

Discontinuation due to adverse events occurs in only 3-7% of participants. 6

Critical Clinical Pearls

Long-term treatment is mandatory: Weight regain occurs rapidly upon discontinuation—this is not a short-term intervention. 2 Tirzepatide must be used in conjunction with lifestyle modifications for optimal results. 1, 2

Non-diabetic patients lose more weight: Tirzepatide produces greater weight loss in non-diabetic individuals (15-20.9%) compared to those with type 2 diabetes (4-6.2%). 2 This difference may partly reflect dissimilarities in gastrointestinal adverse event frequencies. 6

Comparable to bariatric surgery: The weight loss efficacy of tirzepatide is comparable to what has previously only been achieved with bariatric surgery. 2

Superior to other GLP-1 agonists: In head-to-head comparison, tirzepatide produced 5.5 kg more weight loss than semaglutide 1.0 mg at 40 weeks. 2 At 72 weeks, tirzepatide achieves 20.2% mean weight reduction versus 13.7% with semaglutide. 2

Cost Considerations

Average wholesale price is $1,272 per 30-day supply (national average drug acquisition cost $1,017). 1, 2 Insurance coverage varies significantly and may limit access despite clinical appropriateness.