What are the safety and usage guidelines for Zepbound?

Zepbound (Tirzepatide) Safety and Usage Guidelines

What is Zepbound?

Zepbound is tirzepatide, a first-in-class dual GIP/GLP-1 receptor agonist approved specifically for chronic weight management in adults with obesity or overweight with weight-related comorbidities. 1, 2 It is administered as a once-weekly subcutaneous injection available in single-dose prefilled pens and vials. 2

Approved Indications and Patient Selection

• Approved for weight management as an adjunct to reduced-calorie diet and increased physical activity in adults with:

  • Body Mass Index (BMI) ≥30 kg/m² (obesity), OR 3
  • BMI ≥27 kg/m² (overweight) with at least one weight-related comorbidity 3

• Also approved separately (as Mounjaro) for type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control 2, 4

• Patients without type 2 diabetes can safely use tirzepatide for weight management, as demonstrated in real-world studies 3

Dosing and Administration

Start at 2.5 mg subcutaneously once weekly for 4 weeks, then increase by 2.5 mg increments every 4 weeks as tolerated. 2

• Available doses: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg 2
• Maximum dose: 15 mg once weekly 3
• The dose escalation schedule is critical to minimize gastrointestinal adverse events 2, 5
• In real-world practice, only 25.9% of patients reach the maximum 15 mg dose, while most achieve clinically meaningful weight loss at lower doses 3

Expected Efficacy Outcomes

Tirzepatide produces unprecedented weight loss and glycemic control compared to all other single agents, including GLP-1 receptor agonists. 1

Weight Loss Results:

• Mean weight loss at 1 year: 17.2 kg (16.5% body weight reduction) in real-world practice 3
• At 3 years (176 weeks): 12.3% with 5 mg, 18.7% with 10 mg, and 19.7% with 15 mg 5
• 20.7% to 68.4% of patients lose more than 10% of baseline body weight 1
• Semaglutide 2.4 mg produces less weight loss (14.6 kg or 14.1%) compared to tirzepatide 3

Glycemic Control (in patients with type 2 diabetes):

• HbA1c reduction: 1.24% to 2.58% 1
• 23.0% to 62.4% of patients achieve HbA1c <5.7% (normoglycemia) 1
• Superior to semaglutide 1 mg and titrated basal insulin 1, 2

Diabetes Prevention:

• In patients with prediabetes, only 1.3% developed type 2 diabetes at 3 years versus 13.3% with placebo (93% risk reduction) 5
• This protective effect persisted even 17 weeks after stopping treatment (2.4% vs 13.7%) 5

Safety Profile and Adverse Events

The most common adverse events are gastrointestinal, occurring primarily during dose escalation in the first 20 weeks. 5

Common Adverse Events:

• Nausea, diarrhea, decreased appetite, and vomiting (most frequent) 2, 5
• Most gastrointestinal events are mild to moderate in severity 2, 5
• Dose-dependent: higher doses associated with more frequent GI symptoms 1
• The safety profile is consistent with GLP-1 receptor agonists 2

Serious Safety Considerations:

• Low risk of clinically significant or severe hypoglycemia 2
• No increased risk of major adverse cardiovascular events (MACE) 2
• Cardiovascular events tended to be reduced over 2 years, with hazard ratios <1.0 for all cardiovascular endpoints analyzed 1
• No new safety signals identified in 3-year follow-up 5

Withdrawal Rates:

• Relatively low withdrawal rates in active treatment arms despite GI side effects 4
• Real-world persistence: patients included had no gap >30 days in medication supply over 1 year 3

Critical Contraindications and Warnings

Do not use tirzepatide in patients with:

• Personal or family history of medullary thyroid carcinoma 2
• Multiple Endocrine Neoplasia syndrome type 2 2
• History of severe gastrointestinal disease 2

Exercise caution in:

• Patients with history of pancreatitis 2
• Patients with diabetic retinopathy (if using for diabetes) 2
• Pregnant or breastfeeding women 2

Practical Implementation Strategy

Initial Visit:

• Confirm BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidity 3
• Screen for contraindications (thyroid cancer history, MEN2) 2
• Obtain baseline weight, blood pressure, and metabolic parameters 5
• Counsel extensively about expected GI side effects during first 20 weeks 5

Dose Escalation Protocol:

• Week 0-4: 2.5 mg once weekly 2
• Week 5-8: 5 mg once weekly 2
• Week 9-12: 7.5 mg once weekly 2
• Week 13-16: 10 mg once weekly 2
• Week 17-20: 12.5 mg once weekly 2
• Week 21+: 15 mg once weekly (if tolerated and needed) 2

Monitoring Schedule:

• Assess weight, tolerability, and adverse events every 4 weeks during dose escalation 5
• After reaching maintenance dose: monitor every 3 months 5
• Do not advance dose if patient experiencing significant GI symptoms 5
• Most patients achieve adequate weight loss before reaching maximum dose 3

Long-Term Management

Treatment duration of 3 years has been studied and shows sustained efficacy with continued safety. 5

• Weight loss is sustained throughout treatment period 5
• After discontinuation, some weight regain occurs, but diabetes prevention benefits persist for at least 17 weeks 5
• No evidence of tachyphylaxis or tolerance development 1, 5
• Consider indefinite treatment for chronic weight management, as obesity is a chronic disease 5

Comparison to Other Weight Loss Medications

Tirzepatide demonstrates superior weight loss compared to semaglutide 2.4 mg (the previous gold standard). 3

• Tirzepatide: -17.2 kg (-16.5%) at 1 year 3
• Semaglutide 2.4 mg: -14.6 kg (-14.1%) at 1 year 3
• Both medications are used in descriptively similar patient populations 3
• Tirzepatide shows greater improvements in insulin sensitivity and secretion than semaglutide 1

Common Pitfalls to Avoid

• Do not escalate doses too rapidly - this is the primary cause of treatment discontinuation due to GI side effects 5
• Do not skip the 2.5 mg starting dose - the initial 4-week period at 2.5 mg is essential for tolerance 2
• Do not assume all patients need maximum dose - only 25.9% reach 15 mg in real-world practice 3
• Do not discontinue prematurely for mild GI symptoms - most resolve after dose stabilization 5
• Do not use in patients with personal/family history of medullary thyroid cancer 2