What is Zepbound?
Zepbound (tirzepatide) is a once-weekly injectable medication approved by the FDA 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, and it represents the most potent pharmacological weight loss option currently available, achieving mean weight reductions of 20.9% at 72 weeks. 1
Mechanism of Action
Zepbound is a first-in-class dual agonist that activates both GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) receptors 1, 2. These receptors are located in the hypothalamus and brainstem nuclei, where they mediate appetite, satiety, energy intake, and energy expenditure 1. The dual receptor activation provides enhanced metabolic benefits including:
- Delayed gastric emptying 2
- Suppressed appetite through central nervous system pathways 2
- Enhanced glucose-dependent insulin secretion 2
- Reduced glucagon secretion 2
- Increased energy expenditure 2
Importantly, tirzepatide's affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1, yet the dual mechanism produces superior clinical outcomes compared to selective GLP-1 receptor agonists. 2
Weight Loss Efficacy
Tirzepatide produces dose-dependent weight loss, with the 15 mg dose achieving up to 20.9% weight reduction in non-diabetic obese patients at 72 weeks—weight loss comparable to what has previously only been reported with bariatric surgery. 1
Specific efficacy data includes:
- Mean weight reduction of 15% at 72 weeks across all doses 1
- 20.9% weight loss with the 15 mg dose 1
- Nearly 40% of patients achieve ≥25% total body weight loss at 72 weeks with the 15 mg dose 1
- 3-67% of participants achieve at least 10% weight reduction from baseline, depending on dose 1
Tirzepatide demonstrates superior efficacy compared to semaglutide 2.4 mg (Wegovy), producing 20.9% weight loss versus 14.9% with semaglutide at 72 weeks—a 6% absolute advantage. 2, 3
Approved Indications and Dosing
Zepbound is FDA-approved at doses of 5 mg, 10 mg, and 15 mg administered subcutaneously once weekly 1, 4. The medication must be used in conjunction with lifestyle modifications including a reduced-calorie diet and increased physical activity 1.
The FDA-approved starting dose is 5 mg weekly, designed to minimize gastrointestinal adverse events while providing therapeutic benefit, with gradual titration upward every 4 weeks based on tolerance to a maximum dose of 15 mg weekly. 2
Safety Profile
The most common adverse events are gastrointestinal, including:
- Nausea (31% incidence) 1
- Diarrhea (23% incidence) 1
- Vomiting (12% incidence) 1
- Constipation (5% incidence) 1
These side effects are typically mild-to-moderate in severity and occur primarily during dose escalation 1, 5. Slow titration with gradual dose escalation every 4 weeks minimizes gastrointestinal symptoms and improves overall tolerability. 1
Serious but rare risks include pancreatitis and gallbladder disease (cholelithiasis, cholecystitis), though causality has not been definitively established. 1
Absolute Contraindications
Zepbound is absolutely contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2), based on animal studies showing thyroid C-cell tumor formation. 1, 2
Cardiovascular and Metabolic Benefits
Beyond weight loss, tirzepatide produces broader cardiometabolic improvements including:
- Blood pressure reduction through multiple mechanisms 2
- Improved lipid profiles with superior triglyceride reduction 2
- Liver fat reduction with significant decreases in hepatic steatosis and visceral adipose tissue 2
- Improved insulin sensitivity and insulin secretory responses 5
Tirzepatide meets cardiovascular safety criteria with MACE-4 events having hazard ratios <1.0 and upper confidence bounds <1.3, though it does not reduce all-cause mortality compared to usual care. 5
Clinical Considerations
Tirzepatide produces greater weight loss in non-diabetic individuals (15-20.9%) compared to those with diabetes (4-6.2%), suggesting metabolic factors and insulin resistance influence treatment response. 1
Long-term continuous use is necessary to maintain weight loss benefits, as weight regain of one-half to two-thirds of lost weight occurs within 1 year when treatment is discontinued. 1
The average wholesale price is approximately $1,272 for a 30-day supply 1, and insurance authorization may be challenging, particularly for obesity management without diabetes 2.
Comparison to Other Weight Loss Medications
Tirzepatide represents the most effective pharmacological option for weight management currently available, surpassing both semaglutide 2.4 mg (14.9% weight loss) and liraglutide 3.0 mg (5.2-6.1% weight loss). 1, 2, 3
In head-to-head comparison with semaglutide, tirzepatide demonstrated superiority with a mean difference of 4.23 kg (95% CI: 3.22-5.25) in weight loss 2, along with greater waist circumference reduction and superior triglyceride reduction 2.