FDA-Approved Indications for Tirzepatide (Zepbound)
Tirzepatide is FDA-approved for two distinct indications in adults: (1) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (Mounjaro formulation), and (2) for chronic weight management in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity (Zepbound formulation). 1, 2, 3
Type 2 Diabetes Mellitus (Mounjaro)
- Tirzepatide is approved to improve glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise, with HbA1c reductions ranging from -1.87% to -2.59% (-20 to -28 mmol/mol) across the SURPASS clinical trial program 4, 5
- The medication can be used as monotherapy or in combination with other glucose-lowering agents, including metformin, SGLT2 inhibitors, sulfonylureas, and insulin 4, 5
- Tirzepatide demonstrated superior glycemic control compared to GLP-1 receptor agonists (semaglutide 1 mg, dulaglutide 0.75 mg) and insulin in head-to-head trials 4, 5
Chronic Weight Management (Zepbound)
Eligibility Criteria
- BMI ≥30 kg/m² (obesity) qualifies adults for tirzepatide without any additional comorbidity requirement 1, 2
- BMI ≥27 kg/m² (overweight) with at least one weight-related comorbidity qualifies adults for treatment; acceptable comorbidities include type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease 1, 2
Weight Loss Efficacy
- Tirzepatide produces dose-dependent weight loss, with the 15 mg weekly dose achieving approximately 20.9% mean total body weight reduction at 72 weeks in adults with obesity 1, 2, 6
- Approximately 40% of patients achieve ≥25% total body weight loss on the 15 mg dose, representing weight loss magnitude comparable to bariatric surgery 1, 6
- At 3.5 years (long-term follow-up), tirzepatide maintains a mean weight reduction of -15.66% from baseline 6
Mandatory Lifestyle Modifications
- Tirzepatide must be used as an adjunct to a reduced-calorie diet (approximately 500-kcal daily deficit below maintenance requirements) 1, 2
- Patients must engage in ≥150 minutes per week of moderate-intensity physical activity as part of the comprehensive treatment plan 1, 2
- Behavioral counseling and structured lifestyle-modification support are recommended components of therapy 2
Absolute Contraindications
- Personal or family history of medullary thyroid carcinoma (MTC) is an absolute contraindication based on animal studies showing thyroid C-cell tumor formation 1, 2, 5
- Multiple endocrine neoplasia syndrome type 2 (MEN 2) is an absolute contraindication 1, 2, 5
- Pregnancy or breastfeeding is a contraindication due to potential fetal exposure 2
- History of severe hypersensitivity reaction to tirzepatide precludes use 2
Dosing and Administration
- Tirzepatide is administered as a once-weekly subcutaneous injection at any time of day, with or without meals 1, 2
- The FDA-approved starting dose is 5 mg weekly (not 2.5 mg, which is used only for initial tolerability assessment in some protocols), designed to minimize gastrointestinal adverse events while providing therapeutic benefit 1, 2
- Dose escalation occurs every 4 weeks based on tolerance and response, with maximum approved doses of 10 mg or 15 mg weekly 1, 2, 5
Safety Profile and Monitoring
- Gastrointestinal effects (nausea 17-22%, diarrhea 13-16%, vomiting 6-10%, constipation) are the most common adverse events, typically mild-to-moderate and decreasing over time 1, 5, 6
- Pancreatitis and gallbladder disease (cholelithiasis, cholecystitis) have been reported, though causality has not been definitively established; patients should be monitored for persistent severe abdominal pain 1, 2, 5
- Tirzepatide carries minimal intrinsic hypoglycemia risk when used as monotherapy, but risk increases when combined with insulin or sulfonylureas, requiring dose reduction of these agents 1, 5
Renal Considerations
- No dose adjustment is required across all stages of chronic kidney disease, including patients with eGFR <30 mL/min/1.73 m², making tirzepatide suitable for patients with advanced renal impairment 1
Treatment Response Evaluation
- Assess treatment efficacy at 12-16 weeks on the maximum tolerated therapeutic dose (5 mg, 10 mg, or 15 mg) 1, 2
- Discontinue therapy if <5% weight loss is achieved after 3 months at therapeutic dose, as early non-responders are unlikely to benefit from continued treatment 1, 2, 6
- For patients not reaching goals at 16 weeks on maximum tolerated dose, consider intensifying treatment with additional approaches (metabolic surgery, additional pharmacologic agents, structured lifestyle management programs) 1, 2
Long-Term Use and Weight Maintenance
- Lifelong treatment is typically necessary to maintain weight loss benefits, as discontinuation results in regain of one-half to two-thirds of lost weight within 1 year 1, 2
- Early responders (≥5% weight loss after 3 months) should continue medication long-term unless clinical circumstances suggest otherwise 1, 2