Zepbound (Tirzepatide) for Weight Loss
Recommended Usage
Zepbound (tirzepatide) is the most potent FDA-approved medication for weight loss, achieving 20.9% mean weight reduction at 72 weeks with the 15mg dose, significantly outperforming semaglutide (14.9%) and all other anti-obesity medications. 1, 2
Eligibility Criteria
- 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
- Must be used as adjunct to reduced-calorie diet and increased physical activity 1
Dosing and Administration
Subcutaneous injection once weekly with the following titration schedule: 1, 2
- Weeks 0-4: Start at 2.5mg weekly (tolerability dose, not therapeutic)
- Weeks 4-8: Increase to 5mg weekly (first therapeutic dose)
- Weeks 8-12: Increase to 10mg weekly if tolerated
- Weeks 12+: Increase to 15mg weekly (maximum dose) if needed
Key principle: Slow titration every 4 weeks minimizes gastrointestinal side effects 1, 2
Mechanism of Action
Tirzepatide is a dual GIP/GLP-1 receptor agonist that: 1, 3
- Suppresses appetite through hypothalamic and brainstem signaling
- Delays gastric emptying, prolonging satiety
- Enhances glucose-dependent insulin secretion
- Reduces inappropriate glucagon secretion
- Increases energy expenditure
This dual-receptor activation provides superior metabolic benefits compared to GLP-1-only agonists like semaglutide. 1
Expected Weight Loss Outcomes
Dose-dependent efficacy: 1, 2, 4
- 5mg weekly: 15.0% mean weight loss
- 10mg weekly: 19.5% mean weight loss
- 15mg weekly: 20.9% mean weight loss
- 85-91% of patients achieve ≥5% weight loss
- 50-57% achieve ≥20% weight loss with 10-15mg doses
- Weight loss comparable to bariatric surgery outcomes 2
Important caveat: Weight loss is greater in non-diabetic patients (15-20.9%) compared to those with diabetes (4-6.2%) 1, 2
Potential Side Effects
Common Gastrointestinal Effects (Most Frequent)
Nausea, diarrhea, vomiting, and constipation are the predominant side effects, occurring primarily during dose escalation: 1, 2, 6
- Nausea: 17-22% of patients
- Diarrhea: 13-16% of patients
- Vomiting: 6-10% of patients
- Constipation: 5% of patients
These effects are typically mild-to-moderate in severity and decrease over time. 1, 4 Slow titration and dietary modifications (smaller meals, avoiding alcohol and carbonated drinks) help minimize symptoms. 1
Serious but Rare Adverse Events
Pancreatitis: Reported in clinical trials, though causality not definitively established. Monitor for persistent severe abdominal pain. 1, 2
Gallbladder disease: Increased risk of cholelithiasis and cholecystitis. Watch for right upper quadrant pain, especially during rapid weight loss. 1, 2
Perioperative aspiration risk: Retained gastric contents documented even after extended fasting periods (10-14 days). Discuss with anesthesia team before any surgery. 1
Absolute Contraindications
Do NOT use tirzepatide in patients with: 1, 2, 6
- Personal or family history of medullary thyroid cancer
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
Treatment Discontinuation Rates
4.3-7.1% of patients discontinue due to adverse events (primarily gastrointestinal), compared to 2.6% with placebo. 4 This is notably lower than discontinuation rates with semaglutide (34 more per 1000 patients vs placebo). 1
Cardiovascular and Metabolic Benefits
Beyond weight loss, tirzepatide provides: 1, 2, 7
- Blood pressure reduction (may require antihypertensive adjustment)
- Improved lipid profiles (triglyceride reduction, HDL increase)
- Reduced visceral adiposity
- Enhanced insulin sensitivity
- Low hypoglycemia risk when used without insulin or sulfonylureas
Critical Long-Term Considerations
Lifelong Treatment Required
Weight regain occurs rapidly upon discontinuation, regardless of tapering strategy. 1, 2 Patients must understand this is a chronic disease requiring continuous treatment, similar to medications for hypertension or diabetes. 1
Monitoring Schedule
Assess patients every 3 months for: 2
- Continued weight loss progress
- Cardiovascular risk factors
- Medication adherence
- Adverse effects
Evaluate efficacy at 12-16 weeks on maximum tolerated dose: 2
- Expect ≥4-5% body weight loss to justify continuation
- Consider discontinuation if inadequate response
Special Populations
Women of childbearing age: Switch from oral contraceptives to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation, as delayed gastric emptying may affect oral medication absorption. 1
Patients with hypothyroidism: Generally safe, but monitor thyroid function as GLP-1 receptors are expressed in thyroid tissue. 1
Patients on insulin: Reduce basal insulin by 20% when starting tirzepatide to prevent hypoglycemia; strongly consider discontinuing prandial insulin entirely. 1
Practical Prescribing Pitfalls
Common mistake #1: Assessing efficacy too early. The 2.5mg starting dose is for tolerability only—wait until 12-16 weeks on therapeutic doses (5-15mg) before judging effectiveness. 2
Common mistake #2: Arbitrary dose escalation. Only increase dose if weight loss plateaus for 8-12 weeks despite lifestyle adherence, not according to a fixed schedule. 2
Common mistake #3: Combining with other GLP-1 agonists. Never use tirzepatide with semaglutide or other GLP-1 receptor agonists—pharmacologically redundant and potentially harmful. 1
Common mistake #4: Inadequate patient counseling about permanence. Patients must understand this requires lifelong use; discontinuation leads to rapid weight regain. 1, 2
Cost Considerations
Average wholesale price approximately $1,272-$1,600 per 30-day supply. 1, 2 Insurance authorization may be challenging, particularly for obesity without diabetes. Document failed lifestyle modifications for approval. 2